Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis

Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
PLoS Computational Biology (Impact Factor: 4.62). 04/2012; 8(4):e1002482. DOI: 10.1371/journal.pcbi.1002482
Source: PubMed


Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions.

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    • "However, once MOMP is triggered and effector caspases activated, cell death occurs at a rapid, relatively constant rate, in the order of minutes (Albeck et al 2008a, Goldstein et al 2000, Rehm et al 2003). Variability in the timing of cell death is controlled in a non-genetic manner and appears to involve stochastic, naturally occurring differences in the concentrations of positive and negative regulators of apoptosis (Bhola and Simon 2009, Gaudet et al 2012, Spencer et al 2009). Recently, similar dynamics of caspase activation in single cells was demonstrated in glioblastoma cell lines exposed to TRAIL, and these dynamics were shown to be modulated by co-treatment with histone deacetylase inhibitors (Bagci-Onder et al 2012). "
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