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- Title
Coupled positive feedbacks provoke slow induction plus fast switching in apoptosis
- Authors
Choi, Hyung-Seok; Han, Soohee; Yokota, Hiroki; Cho, Kwang-Hyun
- Abstract
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.
- Subjects
CELL death; APOPTOSIS; CANCER cells; ASCITES tumors
- Publication
FEBS Letters, 2007, Vol 581, Issue 14, p2684
- ISSN
0014-5793
- Publication type
Article
- DOI
10.1016/j.febslet.2007.05.016