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PLoS Comput Biol. 2018 Sep 26;14(9):e1006368. doi: 10.1371/journal.pcbi.1006368. eCollection 2018 Sep.

Quantitative single cell analysis uncovers the life/death decision in CD95 network.

Author information

1
Translational Inflammation Research, Otto von Guericke University, Magdeburg, Germany.
2
Process Systems Engineering, Otto von Guericke University, Magdeburg, Germany.
3
Process Systems Engineering, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
4
The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.

Abstract

CD95/Fas/APO-1 is a member of the death receptor family that triggers apoptotic and anti-apoptotic responses in particular, NF-κB. These responses are characterized by a strong heterogeneity within a population of cells. To determine how the cell decides between life and death we developed a computational model supported by imaging flow cytometry analysis of CD95 signaling. Here we show that CD95 stimulation leads to the induction of caspase and NF-κB pathways simultaneously in one cell. The related life/death decision strictly depends on cell-to-cell variability in the formation of the death-inducing complex (DISC) on one side (extrinsic noise) vs. stochastic gene expression of the NF-κB pathway on the other side (intrinsic noise). Moreover, our analysis has uncovered that the stochasticity in apoptosis and NF-kB pathways leads not only to survival or death of a cell, but also causes a third type of response to CD95 stimulation that we termed ambivalent response. Cells in the ambivalent state can undergo cell death or survive which was subsequently validated by experiments. Taken together, we have uncovered how these two competing pathways control the fate of a cell, which in turn plays an important role for development of anti-cancer therapies.

PMID:
30256782
PMCID:
PMC6175528
DOI:
10.1371/journal.pcbi.1006368
[Indexed for MEDLINE]
Free PMC Article

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