Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes (Molecular Biology of the Cell)
May 22, 2013
When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the properties of cells that survive treatment with agonists of two distinct death receptors, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and anti-FasR antibodies. We find that “survivor” cells are highly resistant to a second ligand dose applied 1 d later. Resistance is reversible, resetting after several days of culture in the absence of death ligand. “Reset” cells appear identical...Read more »
Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis (PLOS Computational Biology)
April 26, 2012
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...Read more »
Measuring and Modeling Apoptosis in Single Cells (Cell)
March 18, 2011
Cell death plays an essential role in the development of tissues and organisms, the etiology of disease, and the responses of cells to therapeutic drugs. Here we review progress made over the last decade in using mathematical models and quantitative, often single-cell, data to study apoptosis. We discuss the delay that follows exposure of cells to prodeath stimuli, control of mitochondrial outer membrane permeabilization, switch-like activation of effector caspases , and variability in the timing and probability of death from one cell to the next. Finally, we discuss challenges facing the fields of biochemical modeling and systems pharmacology. [Article Link]Read more »
Systematic calibration of a cell signaling network model (BMC Bioinformatics)
April 23, 2010
Mathematical modeling is being applied to increasingly complex biological systems and datasets; however, the process of analyzing and calibrating against experimental data is often challenging and a rate limiting step in model development. To address this problem, we developed a systematic methodology for calibrating quantitative models of dynamic biological processes and illustrate its utility by validating a model of TRAIL (Tumor necrosis factor Related Apoptosis-Inducing Ligand)-induced cell death. [Article Link]Read more »
Non-genetic cell-to-cell variability and the consequences for pharmacology (Current Opinion in Chemical Biology)
Dec. 1, 2009
Recent advances in single-cell assays have focused attention on the fact that even members of a genetically identical group of cells or organisms in identical environments can exhibit variability in drug sensitivity, cellular response, and phenotype. Underlying much of this variability is stochasticity in gene expression, which can produce unique proteomes even in genetically identical cells. Here we discuss the consequences of non-genetic cell-to-cell variability in the cellular response to drugs and its potential impact for the treatment of human disease. [Article Link]Read more »
Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis (Nature)
May 21, 2009
In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations 1 , 2 , 3 , 4 , 5 , 6 , 7 . In mammalian cells, protein levels also vary 8 , 9 , 10 and individual cells differ widely in their responsiveness to uniform physiological stimuli 11 , 12 , 13 , 14 , 15 . In the case of apoptosis mediated by TRAIL (tumour necrosis factor (TNF)-related apoptosis-inducing ligand) it is common for some cells in a clonal population to die while others survive—a striking divergence in cell fate. Among cells that die,...Read more »
Modeling a snap-action, variable-delay switch controlling extrinsic cell death (PLOS Biology)
Dec. 2, 2008
When exposed to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL), a closely related death ligand and investigational therapeutic, cells enter a protracted period of variable duration in which only upstream initiator caspases are active. A subsequent and sudden transition marks activation of the downstream effector caspases that rapidly dismantle the cell. Thus, extrinsic apoptosis is controlled by an unusual variable-delay, snap-action switch that enforces an unambiguous choice between life and death. To understand how the extrinsic apoptosis switch functions in quantitative terms, we constructed a mathematical model based on a mass-action representation of known reaction pathways. The model...Read more »