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Coupled positive feedbacks provoke slow induction plus fast switching in apoptosis
Author(s) -
Choi Hyung-Seok,
Han Soohee,
Yokota Hiroki,
Cho Kwang-Hyun
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.05.016
Subject(s) - xiap , apoptosis , microbiology and biotechnology , caspase , cell fate determination , inhibitor of apoptosis , caspase 9 , programmed cell death , mechanism (biology) , caspase 3 , chemistry , biology , biochemistry , physics , transcription factor , gene , quantum mechanics
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.