Coupled positive feedbacks provoke slow induction plus fast switching in apoptosis

FEBS Lett. 2007 Jun 12;581(14):2684-90. doi: 10.1016/j.febslet.2007.05.016. Epub 2007 May 21.

Abstract

Apoptosis is a form of a programmed cell death for multicellular organisms to remove unwanted or damaged cells. This critical choice of cellular fate is an all-or-none process, but its dynamics remains unraveled. The switch-like apoptotic decision has to be reliable, and once a pro-apoptotic fate is determined it requires fast and irreversible execution. One of the key regulators in apoptosis is caspase-3. Interestingly, activated caspase-3 quickly executes apoptosis, but it takes considerable time to activate it. Here, we have analyzed this "slow induction plus fast switching" mechanism of caspase-3 through mathematical modeling and computational simulation. First, we have shown that two positive feedbacks, composed of caspase-8 and XIAP, are essential for the "slow induction plus fast switching" behavior of caspase-3. Second, we have found that XIAP in the feedback loops primarily regulates induction time of caspase-3. In many cancer cells activation of caspase-3 is suppressed. Our results suggest that reinforcement of the positive feedback by XIAP, which relieves XIAP-mediated caspase-3 inhibition, might favor a pro-apoptotic cellular fate.

Publication types

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

MeSH terms

  • Apoptosis / physiology*
  • Caspase 3 / metabolism*
  • Computer Simulation
  • Feedback, Physiological
  • Models, Biological
  • Signal Transduction / physiology*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*

Substances

  • X-Linked Inhibitor of Apoptosis Protein
  • Caspase 3