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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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Bibliographic Details
Main Authors: Neumann, Leo (Author) , Pforr, Carina (Author) , Beaudouin, Joel (Author) , Pappa, Alexander (Author) , Fricker, Nicolai Benjamin (Author) , Krammer, Peter H. (Author) , Lavrik, Inna N. (Author) , Eils, Roland (Author)
Format: Article (Journal)
Language:English
Published: 9 March 2010
In: Molecular systems biology
Year: 2010, Volume: 6, Issue: 1, Pages: 1-17
ISSN:1744-4292
DOI:10.1038/msb.2010.6
Online Access: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
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Author Notes:Leo Neumann, Carina Pforr, Joel Beaudouin, Alexander Pappa, Nicolai Fricker, Peter H Krammer, Inna N Lavrik and Roland Eils
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Summary: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.
Item Description:Gesehen am 12.05.2023
Physical Description:Online Resource
ISSN:1744-4292
DOI:10.1038/msb.2010.6

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