Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL
Cellular FADD-like interleukin-1β-converting enzyme inhibitory proteins (c-FLIPs; isoforms c-FLIP long [c-FLIPL], c-FLIP short [c-FLIPS], and c-FLIP Raji [c-FLIPR]) regulate caspase-8 activation and death receptor (DR)-induced apoptosis. In this study, using a combination of mathematical modeling, i...
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| Main Authors: | , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 09 2010
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| In: |
The journal of cell biology
Year: 2010, Volume: 190, Issue: 3, Pages: 377-389 |
| ISSN: | 1540-8140 |
| DOI: | 10.1083/jcb.201002060 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1083/jcb.201002060 Verlag, lizenzpflichtig, Volltext: https://rupress.org/jcb/article/190/3/377/36119/Model-based-dissection-of-CD95-signaling-dynamics 
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| Author Notes: | Nicolai Fricker, Joel Beaudouin, Petra Richter, Roland Eils, Peter H. Krammer, and Inna N. Lavrik |
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| 520 | |a Cellular FADD-like interleukin-1β-converting enzyme inhibitory proteins (c-FLIPs; isoforms c-FLIP long [c-FLIPL], c-FLIP short [c-FLIPS], and c-FLIP Raji [c-FLIPR]) regulate caspase-8 activation and death receptor (DR)-induced apoptosis. In this study, using a combination of mathematical modeling, imaging, and quantitative Western blots, we present a new mathematical model describing caspase-8 activation in quantitative terms, which highlights the influence of c-FLIP proteins on this process directly at the CD95 death-inducing signaling complex. We quantitatively define how the stoichiometry of c-FLIP proteins determines sensitivity toward CD95-induced apoptosis. We show that c-FLIPL has a proapoptotic role only upon moderate expression in combination with strong receptor stimulation or in the presence of high amounts of one of the short c-FLIP isoforms, c-FLIPS or c-FLIPR. Our findings resolve the present controversial discussion on the function of c-FLIPL as a pro- or antiapoptotic protein in DR-mediated apoptosis and are important for understanding the regulation of CD95-induced apoptosis, where subtle differences in c-FLIP concentrations determine life or death of the cells. | ||
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