Quantitative Analysis of Pathways Controlling Extrinsic Apoptosis in Single Cells

John Albeck, John M. Burke, Bree B. Aldridge, Mingsheng Zhang, Douglas A. Lauffenburger, Peter K. Sorger

Research output: Contribution to journalArticle

262 Scopus citations

Abstract

Apoptosis in response to TRAIL or TNF requires the activation of initiator caspases, which then activate the effector caspases that dismantle cells and cause death. However, little is known about the dynamics and regulatory logic linking initiators and effectors. Using a combination of live-cell reporters, flow cytometry, and immunoblotting, we find that initiator caspases are active during the long and variable delay that precedes mitochondrial outer membrane permeabilization (MOMP) and effector caspase activation. When combined with a mathematical model of core apoptosis pathways, experimental perturbation of regulatory links between initiator and effector caspases reveals that XIAP and proteasome-dependent degradation of effector caspases are important in restraining activity during the pre-MOMP delay. We identify conditions in which restraint is impaired, creating a physiologically indeterminate state of partial cell death with the potential to generate genomic instability. Together, these findings provide a quantitative picture of caspase regulatory networks and their failure modes.

Original languageEnglish (US)
Pages (from-to)11-25
Number of pages15
JournalMolecular Cell
Volume30
Issue number1
DOIs
StatePublished - Apr 11 2008
Externally publishedYes

Keywords

  • CELLCYCLE
  • SYSBIO

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Albeck, J., Burke, J. M., Aldridge, B. B., Zhang, M., Lauffenburger, D. A., & Sorger, P. K. (2008). Quantitative Analysis of Pathways Controlling Extrinsic Apoptosis in Single Cells. Molecular Cell, 30(1), 11-25. https://doi.org/10.1016/j.molcel.2008.02.012