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Noisy-threshold control of cell death.

Vilar JM - BMC Syst Biol (2010)

Bottom Line: 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.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.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.

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Affiliation: Biophysics 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

ABSTRACT

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.

Show MeSH
Threshold distributions. The inferred ATP threshold distributions are shown for three different levels of expression of the oncogene Bcl-xL. The values of the parameters μ and σ that characterize the threshold distributions, given by , are the same as in Figure 2.
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Figure 3: Threshold distributions. The inferred ATP threshold distributions are shown for three different levels of expression of the oncogene Bcl-xL. The values of the parameters μ and σ that characterize the threshold distributions, given by , are the same as in Figure 2.

Mentions: The initial distributions inferred from the experimental data (Figure 3), by choosing the parameters μ and σ to reproduce the observed behavior, indicate that, as Bcl-xL expression increases, the thresholds shift on average toward lower values of the ATP level, consistent with the well-known antiapoptotic properties of Bcl-xL. At the same time, the distributions increase their relative spread, resulting in higher cell-to-cell variability for higher Bcl-xL expression (Figure 4).


Noisy-threshold control of cell death.

Vilar JM - BMC Syst Biol (2010)

Threshold distributions. The inferred ATP threshold distributions are shown for three different levels of expression of the oncogene Bcl-xL. The values of the parameters μ and σ that characterize the threshold distributions, given by , are the same as in Figure 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992511&req=5

Figure 3: Threshold distributions. The inferred ATP threshold distributions are shown for three different levels of expression of the oncogene Bcl-xL. The values of the parameters μ and σ that characterize the threshold distributions, given by , are the same as in Figure 2.
Mentions: The initial distributions inferred from the experimental data (Figure 3), by choosing the parameters μ and σ to reproduce the observed behavior, indicate that, as Bcl-xL expression increases, the thresholds shift on average toward lower values of the ATP level, consistent with the well-known antiapoptotic properties of Bcl-xL. At the same time, the distributions increase their relative spread, resulting in higher cell-to-cell variability for higher Bcl-xL expression (Figure 4).

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biophysics 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

ABSTRACT

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.

Show MeSH