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      Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling

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          Summary

          Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. We furthermore show that without extrinsic noise in the core module, variable (including noisy) signals would be faithfully reproduced downstream, but the within-module extrinsic variability distorts these signals and leads to a drastic reduction in the mutual information between incoming signal and ERK activity.

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          Highlights

          • Active MEK and ERK levels differ profoundly among genetically identical cells
          • A statistical framework is developed to identify the causes of this variability
          • Analysis shows that extrinsic noise upstream MEK-ERK module causes cell variability
          • Within-module extrinsic variability distorts signals

          Abstract

          Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells, but the origins of such variability remain poorly understood. Filippi et al. present a comprehensive analysis of cell-to-cell variability in the ERK phosphorylation process by combining a statistical modeling approach with high-throughput image cytometry measurements.

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          Most cited references 59

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          Phenotypic diversity, population growth, and information in fluctuating environments.

          Organisms in fluctuating environments must constantly adapt their behavior to survive. In clonal populations, this may be achieved through sensing followed by response or through the generation of diversity by stochastic phenotype switching. Here we show that stochastic switching can be favored over sensing when the environment changes infrequently. The optimal switching rates then mimic the statistics of environmental changes. We derive a relation between the long-term growth rate of the organism and the information available about its fluctuating environment.
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            Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor.

            A single cell clonal line which responds reversibly to nerve growth factor (NGF) has been established from a transplantable rat adrenal pheochromocytoma. This line, designated PC12, has a homogeneous and near-diploid chromosome number of 40. By 1 week's exposure to NGF, PC12 cells cease to multiply and begin to extend branching varicose processes similar to those produced by sympathetic neurons in primary cell culture. By several weeks of exposure to NGF, the PC12 processes reach 500-1000 mum in length. Removal of NGF is followed by degeneration of processes within 24 hr and by resumption of cell multiplication within 72 hr. PC12 cells grown with or without NGF contain dense core chromaffin-like granules up to 350 nm in diameter. The NGF-treated cells also contain small vesicles which accumulate in process varicosities and endings. PC12 cells synthesize and store the catecholamine neurotransmitters dopamine and norepinephrine. The levels (per mg of protein) of catecholamines and of the their synthetic enzymes in PC12 cells are comparable to or higher than those found in rat adrenals. NGF-treatment of PC12 cells results in no change in the levels of catecholamines or of their synthetic enzymes when expressed on a per cell basis, but does result in a 4- to 6-fold decrease in levels when expressed on a per mg of protein basis. PC12 cells do not synthesize epinephrine and cannot be induced to do so by treatment with dexamethasone. The PC12 cell line should be a useful model system for neurobiological and neurochemical studies.
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              Oscillations in NF-kappaB signaling control the dynamics of gene expression.

              Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                02 June 2016
                14 June 2016
                02 June 2016
                : 15
                : 11
                : 2524-2535
                Affiliations
                [1 ]Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK
                [2 ]Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK
                [3 ]Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK
                [4 ]Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan
                [5 ]CREST, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan
                [6 ]Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
                Author notes
                []Corresponding author m.stumpf@ 123456imperial.ac.uk
                Article
                S2211-1247(16)30592-7
                10.1016/j.celrep.2016.05.024
                4914773
                27264188
                © 2016 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Cell biology

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