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

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

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Title: Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis
Author: Spencer, Sabrina L.; Gaudet, Suzanne; Chen, William Wei-Lun; Sorger, Peter Karl

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Citation: Gaudet, Suzanne, Sabrina L. Spencer, William W. Chen, and Peter K. Sorger. 2012. Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis. PLoS Computational Biology 8(4): e1002482.
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Abstract: 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.
Published Version: doi:10.1371/journal.pcbi.1002482
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343095/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10370566
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