Noisy-threshold control of cell death
1Biophysics Unit, CSIC-UPV/EHU and Department of Biochemistry and Molecular Biology, University of the Basque Country, PO Box 644, 48080 Bilbao, Spain. j.vilar@ikerbasque.org
Background:
Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.
Results:
Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-xL and directly links adaptation with noise in an ATP threshold below which cells die.
Conclusions:
These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.
Insights
Cellular adaptation to death signals involves variability and threshold control. Oncogenes like Bcl-xL actively regulate this cell-cell variability and adaptation extent.
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Systems Biology
Background:
- Cellular responses to death stimuli involve distinct phases: lag, extensive death, and adaptation.
- Dysregulation of these cellular events contributes to various diseases.
- Improper adaptation allows cell survival under lethal conditions, leading to therapeutic failure, particularly in cancer treatments.
Purpose of the Study:
- To investigate the underlying mechanisms of cellular adaptation to death-promoting stimuli.
- To model the quantitative aspects of T-cell apoptosis and adaptation.
- To explore the role of intracellular variability and threshold-based control in cellular responses.
Main Methods:
- Development of a quantitative model for T-cell apoptosis.
- Integration of intracellular variability with a threshold-based control mechanism.
- Analysis of experimental data for varying expression levels of the oncogene Bcl-xL.
Main Results:
- Cellular responses naturally emerge from the interaction of intracellular variability and threshold-based control.
- The model accurately predicts experimental observations for different Bcl-xL expression levels.
- Adaptation is linked to cellular noise and an ATP threshold, below which cells undergo apoptosis.
Conclusions:
- Oncogenes such as Bcl-xL play a role beyond regulating cell death rates.
- Bcl-xL actively controls cell-cell variability and the degree of adaptation.
- Understanding these mechanisms offers insights into disease pathogenesis and therapeutic resistance.
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