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Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis

Abstract

In microorganisms, noise in gene expression gives rise to cell-to-cell variability in protein concentrations1,2,3,4,5,6,7. In mammalian cells, protein levels also vary8,9,10 and individual cells differ widely in their responsiveness to uniform physiological stimuli11,12,13,14,15. 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, the time between TRAIL exposure and caspase activation is highly variable. Here we image sister cells expressing reporters of caspase activation and mitochondrial outer membrane permeabilization after exposure to TRAIL. We show that naturally occurring differences in the levels or states of proteins regulating receptor-mediated apoptosis are the primary causes of cell-to-cell variability in the timing and probability of death in human cell lines. Protein state is transmitted from mother to daughter, giving rise to transient heritability in fate, but protein synthesis promotes rapid divergence so that sister cells soon become no more similar to each other than pairs of cells chosen at random. Our results have implications for understanding ‘fractional killing’ of tumour cells after exposure to chemotherapy, and for variability in mammalian signal transduction in general.

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Figure 1: The time-to-death is highly correlated between HeLa sister cells, but correlation decays as a function of time since division.
Figure 2: Endogenous variation in the concentrations of apoptotic regulators is sufficient to explain variability in Td.
Figure 3: A single time-dependent process upstream of MOMP predicts the time-to-death.
Figure 4: No single protein predicts T d under normal conditions but overexpression can increase predictability.

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Acknowledgements

We thank D. Flusberg, S. Govind, L. Kleiman, A. Letai, B. Millard, R. Milo, T. Norman, J. Paulsson and R. Ward for their help. This work was supported by National Institute of Health (NIH grants) GM68762 and CA112967.

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Correspondence to Peter K. Sorger.

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P.K.S. is a Director of Applied Precision Inc., manufacturers of the microscopes used in this study.

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Spencer, S., Gaudet, S., Albeck, J. et al. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459, 428–432 (2009). https://doi.org/10.1038/nature08012

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