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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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Bibliographic Details
Main Authors: Fricker, Nicolai Benjamin (Author) , Beaudouin, Joël (Author) , Richter, Petra (Author) , Eils, Roland (Author) , Krammer, Peter H. (Author) , Lavrik, Inna N. (Author)
Format: Article (Journal)
Language:English
Published: August 09 2010
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
Description
Summary: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.
Item Description:Gesehen am 24.10.2023
Physical Description:Online Resource
ISSN:1540-8140
DOI:10.1083/jcb.201002060

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