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Mathematical modeling identified c-FLIP as an apoptotic switch in death receptor induced apoptosis

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Abstract

Apoptosis is an essential process to get rid of injured or unwanted cells. In this study, we proposed a mathematical modeling for death receptor mediated apoptosis to investigate the role of c-FLIP in controlling the balance between apoptosis and survival. In order to get insight into how NF-kappa B mediated pro-survival pathway affects the outcome of our modeling, we implemented reduced models without taking such regulation into consideration. Our simulation revealed that c-FLIP could act as a pivotal death or life switch and this switch-like behavior is bistable, irreversible, and robust. We introduce a new term, probability apoptosis, to delineate the likelihood in occurrence of apoptosis events. This simulation system is plausible and may offer several valuable clinical indications for the abnormal apoptosis related disease, such as cancer.

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Abbreviations

c-FLIP:

Cellular-FLICE inhibitory protein

DISC:

Death inducing signaling complex

DD:

Death domain

DR:

Death receptor

DED:

Death effector domain

TNF:

Tumor necrosis factor

Bcl-2:

B cell lymphoma 2

IAP:

Inhibitor of apoptosis protein

TRAF:

Tumor necrosis factor-receptor associated factor

RIP:

Receptor interacting protein

FADD:

Fas-associated DED

Casp n:

Pro-caspase n

Casp n*:

Activated caspase n

NF-kappa B*:

Activated form of NF-kappa B

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (No. 30700357) and Natural Science Foundation of Shandong Province (No. Q2006C06).

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Shandong University, Jinan, 250012, China

    Lihui Han

  2. Shandong Electric Power Research Institute, Jinan, 250002, China

    Yishu Zhao

  3. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, 250012, China

    Xiaoqing Jia

Authors
  1. Lihui Han
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  2. Yishu Zhao
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  3. Xiaoqing Jia
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Correspondence to Lihui Han.

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Lihui Han and Yishu Zhao contributed equally to this work.

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Han, L., Zhao, Y. & Jia, X. Mathematical modeling identified c-FLIP as an apoptotic switch in death receptor induced apoptosis. Apoptosis 13, 1198–1204 (2008). https://doi.org/10.1007/s10495-008-0252-3

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