Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL

• Verfasst von: Fricker, Nicolai Benjamin [VerfasserIn]
• Verfasst von: Beaudouin, Joël [VerfasserIn]
• Verfasst von: Richter, Petra [VerfasserIn]
• Verfasst von: Eils, Roland [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Lavrik, Inna N. [VerfasserIn]
• Titel: Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL
• Verf.angabe: Nicolai Fricker, Joel Beaudouin, Petra Richter, Roland Eils, Peter H. Krammer, and Inna N. Lavrik
• E-Jahr: 2010
• Jahr: August 09 2010
• Umfang: 13 S.
• Fussnoten: Gesehen am 24.10.2023
• Titel Quelle: Enthalten in: The journal of cell biology
• Ort Quelle: New York, NY : Rockefeller Univ. Press, 1962
• Jahr Quelle: 2010
• Band/Heft Quelle: 190(2010), 3, Seite 377-389
• ISSN Quelle: 1540-8140
• DOI: doi:10.1083/jcb.201002060
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1867422751

Abstract

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.