Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis

Mol Syst Biol. 2011 Nov 22:7:553. doi: 10.1038/msb.2011.85.

Abstract

Receptor-mediated apoptosis proceeds via two pathways: one requiring only a cascade of initiator and effector caspases (type I behavior) and the second requiring an initiator-effector caspase cascade and mitochondrial outer membrane permeabilization (type II behavior). Here, we investigate factors controlling type I versus II phenotypes by performing Lyapunov exponent analysis of an ODE-based model of cell death. The resulting phase diagrams predict that the ratio of XIAP to pro-caspase-3 concentrations plays a key regulatory role: type I behavior predominates when the ratio is low and type II behavior when the ratio is high. Cell-to-cell variability in phenotype is observed when the ratio is close to the type I versus II boundary. By positioning multiple tumor cell lines on the phase diagram we confirm these predictions. We also extend phase space analysis to mutations affecting the rate of caspase-3 ubiquitylation by XIAP, predicting and showing that such mutations abolish all-or-none control over activation of effector caspases. Thus, phase diagrams derived from Lyapunov exponent analysis represent a means to study multi-factorial control over a complex biochemical pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / physiology*
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Phenotype
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Ubiquitination
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*

Substances

  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Caspase 3