Noisy-threshold control of cell death.
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.
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
Jose M G
JM
Vilar
D000255:Adenosine Triphosphate / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D005786:Gene Expression Regulation; D008954:Models, Biological; D013997:Time Factors; D051020:bcl-X Protein / Q000378:metabolism
D051020:bcl-X Protein; D000255:Adenosine Triphosphate