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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.

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Noise-threshold model of apoptosis. (A) The cartoon illustrates the cellular processes that serve as a basis for the model. The metabolic state of the cell determines the intracellular ATP level. The ATP level controls negatively the release of cytochrome c (cyt c) from mitochondria into the cytosol, which promotes apoptosis. Antiapoptotic proteins such as Bcl-xL prevent the release of cytochrome c and can compensate for low ATP levels. (B) The model assumes that each individual cell has a given threshold for the ATP level that separates death from survival. Cells that survive, emphasized in blue, are those with thresholds below the ATP level (set here at ~1 fmol/cell for illustrative purposes).
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Figure 1: Noise-threshold model of apoptosis. (A) The cartoon illustrates the cellular processes that serve as a basis for the model. The metabolic state of the cell determines the intracellular ATP level. The ATP level controls negatively the release of cytochrome c (cyt c) from mitochondria into the cytosol, which promotes apoptosis. Antiapoptotic proteins such as Bcl-xL prevent the release of cytochrome c and can compensate for low ATP levels. (B) The model assumes that each individual cell has a given threshold for the ATP level that separates death from survival. Cells that survive, emphasized in blue, are those with thresholds below the ATP level (set here at ~1 fmol/cell for illustrative purposes).

Mentions: Apoptosis can be triggered by a variety of internal or external stimuli, such as specific death signals, lack of growth factors, DNA damage, and different types of stress [3]. These stimuli frequently converge with the metabolic state of the cell into the mitochondrial pathway, which promotes apoptosis through activation of the caspase cascade by releasing cytochrome c into the cytosol [3-5]. Low intracellular ATP levels favor the release of cytochrome c, resulting in high apoptotic rates [6,7]. In this way, the absence of nutrients or signals that stimulate metabolism triggers apoptosis in a wide variety of cell types (Figure 1A).


Noisy-threshold control of cell death.

Vilar JM - BMC Syst Biol (2010)

Noise-threshold model of apoptosis. (A) The cartoon illustrates the cellular processes that serve as a basis for the model. The metabolic state of the cell determines the intracellular ATP level. The ATP level controls negatively the release of cytochrome c (cyt c) from mitochondria into the cytosol, which promotes apoptosis. Antiapoptotic proteins such as Bcl-xL prevent the release of cytochrome c and can compensate for low ATP levels. (B) The model assumes that each individual cell has a given threshold for the ATP level that separates death from survival. Cells that survive, emphasized in blue, are those with thresholds below the ATP level (set here at ~1 fmol/cell for illustrative purposes).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Noise-threshold model of apoptosis. (A) The cartoon illustrates the cellular processes that serve as a basis for the model. The metabolic state of the cell determines the intracellular ATP level. The ATP level controls negatively the release of cytochrome c (cyt c) from mitochondria into the cytosol, which promotes apoptosis. Antiapoptotic proteins such as Bcl-xL prevent the release of cytochrome c and can compensate for low ATP levels. (B) The model assumes that each individual cell has a given threshold for the ATP level that separates death from survival. Cells that survive, emphasized in blue, are those with thresholds below the ATP level (set here at ~1 fmol/cell for illustrative purposes).
Mentions: Apoptosis can be triggered by a variety of internal or external stimuli, such as specific death signals, lack of growth factors, DNA damage, and different types of stress [3]. These stimuli frequently converge with the metabolic state of the cell into the mitochondrial pathway, which promotes apoptosis through activation of the caspase cascade by releasing cytochrome c into the cytosol [3-5]. Low intracellular ATP levels favor the release of cytochrome c, resulting in high apoptotic rates [6,7]. In this way, the absence of nutrients or signals that stimulate metabolism triggers apoptosis in a wide variety of cell types (Figure 1A).

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