  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. 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. 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.
