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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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
9 March 2010
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| 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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| 520 | |a 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. | ||
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