Coupled positive feedbacks provoke slow induction plus fast switching in apoptosis.
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.
Choi
Hyung-Seok
HS
Interdisciplinary Program in Bioinformatics, Seoul National University, Gwanak-Gu, Seoul, Republic of Korea.
Han
Soohee
S
Yokota
Hiroki
H
Cho
Kwang-Hyun
KH
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D003198:Computer Simulation; D025461:Feedback, Physiological; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3