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This article is part of the supplement: Selected articles from the 4th International Conference on Computational Systems Biology (ISB 2010)

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A trigger model of apoptosis induced by tumor necrosis factor signaling

Chang Gu1, Junjie Zhang2, Yingyu Chen34 and Jinzhi Lei5*

Author affiliations

1 School of Mathematical Sciences, Peking University, Beijing 100871, China

2 The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China

3 Laboratory of Medical Immunology, School of Basic Medical Science, Health Science Center, Peking University, 38 Xueyuan Road, Beijing 100083, China

4 Center for Human Disease Genomics, Peking University, 38 Xueyuan Road, Beijing 100083, China

5 Zhou Pei-Yuan Center for Applied Mathematics, Tsinghua University, Beijing 100084, China

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Citation and License

BMC Systems Biology 2011, 5(Suppl 1):S13  doi:10.1186/1752-0509-5-S1-S13

Published: 20 June 2011



The ability of living cells to respond appropriately to apoptosis signals is crucial for the proper development and homeostasis of multicellular organisms. For example, viable cells must be stable enough to appropriately respond to apoptosis signaling so that an irreversible death program is only induced when apoptosis signaling reaches a certain threshold. Previous studies have introduced bistability models in which signaling by caspase-3 activity represents a key regulator of cell fate in response to apoptosis stimuli.


In this study, apoptosis induced by tumor necrosis factor (TNF) signaling is investigated, and a mathematical model without the requirement for bistability is proposed. In this model, rapid degradation of the active forms of caspases -8 and -3 are included, and TNF-signaling is found to induce a pulse of caspase-3 activation and trigger an irreversible death program. This result agrees with experimental observations. The ability of a cell to respond to, or resist, apoptosis stimuli is also discussed. Furthermore, the activation efficiencies of caspases -8 and -3 that are essential to a cell’s response to extracellular apoptosis stimuli are defined. Based on the simulations performed, it is observed that activation efficiencies must be sufficiently sensitive to appropriately compromise a cell’s resistance and effectiveness in response to apoptosis stimuli.


Our results suggest that bistability may not be a necessary condition for the induction of apoptosis by TNF signaling. Rather, a sharp increase in caspase-3 activity might be sufficient to trigger the induction of an irreversible death program. Accordingly, regulation of caspase activity and degradation of active caspases is essential for a cell’s response to apoptosis stimuli.