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    FEBS Lett. 2007 Jun 12;581(14):2684-90. Epub 2007 May 21.

    Coupled positive feedbacks provoke slow induction plus fast switching in apoptosis.

    Choi HS, Han S, Yokota H, Cho KH.

    Interdisciplinary Program in Bioinformatics, Seoul National University, Gwanak-Gu, Seoul, Republic of Korea.

    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.

    PMID: 17532319 [PubMed - indexed for MEDLINE]

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