Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8 ka
Procaspase-8 recruitment to TNFR Complex2~FLIP
Procaspase-8 recruitment to TNFR Complex2~FLIP ka
Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8
FLIP recruitment to TNFR Complex2~Procaspase-8
RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8 ka
nuclear IkappaBalpha~NF-kappaB complex degradation
Procaspase-8 recruitment to TNFR Complex2~Procaspase-8
Procaspase-8 recruitment to TNFR Complex2~Procaspase-8 ka
Procaspase-8 recruitment to TNFR Complex2 ka
Procaspase-8 recruitment to TNFR Complex2
IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 ka
RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8
IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2
FLIP recruitment to TNFR Complex2~FLIP ka
TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation
IkappaBalpha binding NF-kappaB in nucleus ka
release and degradation of bound IkappaBalpha
nuclear IkappaBalpha~NF-kappaB complex degradation ka
This model is from the article: Heterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli Schliemann M, Bullinger E, Borchers S, Allgower F, Findeisen R, Scheurich P. BMC Syst Biol. 2011 Dec 28;5(1):204. 22204418 , Abstract: BACKGROUND: Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. RESULTS: This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. CONCLUSIONS: Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity. Note: SBML model generated from Matlab system description on 12-July-2011 21:08:15 by exportSBML Copyright Eric Bullinger 2007-2011
free nuclear IkappaBalpha degradation ka
negative feedback loop Caspase-3 on TNFR Complex1 ka
IkappaBalpha binding NF-kappaB in nucleus
TNFR Complex2~Procaspase-8~Procaspase-8 degradation
IkappaBalpha~NF-kappaB complex degradation ka
TNFR Complex2~FLIP~Procaspase-8 degradation
Caspase-8 activation by TNFR Complex2 ka
FLIP recruitment to TNFR Complex2~Procaspase-8 ka
IkappaBalpha~NF-kappaB complex degradation
TNFR Complex2~Procaspase-8 degradation ka
TNFR Complex2~FLIP~Procaspase-8 degradation ka
TNFR Complex2~Procaspase-8~Procaspase-8 degradation ka
negative feedback loop Caspase-3 on TNFR Complex1
TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation ka
release and degradation of bound IkappaBalpha ka