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Dynamics within the CD95 death-inducing signaling complex decide life and death of cells

This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-?B. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-?B signaling. Systematic model...

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Bibliographische Detailangaben
Hauptverfasser: Neumann, Leo (VerfasserIn) , Pforr, Carina (VerfasserIn) , Beaudouin, Joel (VerfasserIn) , Pappa, Alexander (VerfasserIn) , Fricker, Nicolai Benjamin (VerfasserIn) , Krammer, Peter H. (VerfasserIn) , Lavrik, Inna N. (VerfasserIn) , Eils, Roland (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 9 March 2010
In: Molecular systems biology
Year: 2010, Jahrgang: 6, Heft: 1, Pages: 1-17
ISSN:1744-4292
DOI:10.1038/msb.2010.6
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/msb.2010.6
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.1038/msb.2010.6
Volltext
Verfasserangaben:Leo Neumann, Carina Pforr, Joel Beaudouin, Alexander Pappa, Nicolai Fricker, Peter H Krammer, Inna N Lavrik and Roland Eils
Beschreibung
Zusammenfassung:This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-?B. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-?B signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIPL cleavage in the death-inducing signaling complex (DISC) and the NF-?B pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-?B pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIPL and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-?B signaling.
Beschreibung:Gesehen am 12.05.2023
Beschreibung:Online Resource
ISSN:1744-4292
DOI:10.1038/msb.2010.6

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