Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.

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...

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Autores principales:	Suzanne Gaudet, Sabrina L Spencer, William W Chen, Peter K Sorger
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1a70568a02dd49bdba33d80b7ca035f9
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spelling	oai:doaj.org-article:1a70568a02dd49bdba33d80b7ca035f92021-11-18T05:51:23ZExploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.1553-734X1553-735810.1371/journal.pcbi.1002482https://doaj.org/article/1a70568a02dd49bdba33d80b7ca035f92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22570596/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Stochastic 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.Suzanne GaudetSabrina L SpencerWilliam W ChenPeter K SorgerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 4, p e1002482 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Suzanne Gaudet Sabrina L Spencer William W Chen Peter K Sorger Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
description	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.
format	article
author	Suzanne Gaudet Sabrina L Spencer William W Chen Peter K Sorger
author_facet	Suzanne Gaudet Sabrina L Spencer William W Chen Peter K Sorger
author_sort	Suzanne Gaudet
title	Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
title_short	Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
title_full	Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
title_fullStr	Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
title_full_unstemmed	Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
title_sort	exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/1a70568a02dd49bdba33d80b7ca035f9
work_keys_str_mv	AT suzannegaudet exploringthecontextualsensitivityoffactorsthatdeterminecelltocellvariabilityinreceptormediatedapoptosis AT sabrinalspencer exploringthecontextualsensitivityoffactorsthatdeterminecelltocellvariabilityinreceptormediatedapoptosis AT williamwchen exploringthecontextualsensitivityoffactorsthatdeterminecelltocellvariabilityinreceptormediatedapoptosis AT peterksorger exploringthecontextualsensitivityoffactorsthatdeterminecelltocellvariabilityinreceptormediatedapoptosis
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Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis.

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