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

PLoS Computational Biology
Suzanne GaudetPeter K Sorger

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 sensi...Continue Reading

References

May 1, 1990·Molecular & General Genetics : MGG·C MaierE Bremer
Apr 1, 1996·Cancer Genetics and Cytogenetics·K Heinonen, E Mahlamäki
Feb 4, 1997·Proceedings of the National Academy of Sciences of the United States of America·H H McAdams, A Arkin
May 2, 1998·The EMBO Journal·C ScaffidiM E Peter
Feb 28, 2002·Apoptosis : an International Journal on Programmed Cell Death·A T M VaughanM J Villalobos
Aug 17, 2002·Science·Michael B ElowitzPeter S Swain
Aug 17, 2004·Science·Nathalie Q BalabanStanislas Leibler
Mar 26, 2005·Science·Nitzan RosenfeldMichael B Elowitz
Dec 20, 2005·Cell·Ido GoldingEdward C Cox
May 6, 2006·Methods in Molecular Biology·Michael J VillalobosAndrew T M Vaughan
Nov 24, 2006·Nature·Alex SigalUri Alon
Feb 27, 2007·Cell·Oliver J Rando, Kevin J Verstrepen
Nov 6, 2007·Water Science and Technology : a Journal of the International Association on Water Pollution Research·D Brockmann, E Morgenroth
Dec 22, 2007·Nature·Ian ChambersAustin Smith
Jan 22, 2008·Nature Immunology·Elaine Dzierzak, Nancy A Speck
Apr 15, 2008·Molecular Cell·John G AlbeckPeter K Sorger
Dec 5, 2008·PLoS Biology·John G AlbeckPeter K Sorger
Dec 23, 2008·Proceedings of the National Academy of Sciences of the United States of America·François St-Pierre, Drew Endy
Apr 14, 2009·Nature·Sabrina L SpencerPeter K Sorger
Apr 22, 2009·PloS One·Ariel Aharon CohenUri Alon
Oct 22, 2009·Science Signaling·Timothy K LeeMarkus W Covert
Feb 19, 2010·Nature·Arjun RajAlexander van Oudenaarden
Jul 20, 2010·Oncogene·M M Lovric, C J Hawkins
Nov 10, 2011·Molecular Systems Biology·Nagarjuna NagarajMatthias Mann
Nov 10, 2011·Molecular Systems Biology·Martin BeckRuedi Aebersold
Nov 24, 2011·Molecular Systems Biology·Bree B AldridgePeter K Sorger

❮ Previous
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Citations

Jan 31, 2014·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Heinrich J HuberJochen H M Prehn
Jun 27, 2014·Journal of the Royal Society, Interface·Maciej DobrzyńskiBoris N Kholodenko
Oct 1, 2014·Proceedings of the National Academy of Sciences of the United States of America·K Wesley OvertonClifford L Wang
Sep 10, 2013·Nature Chemical Biology·Mohammad Fallahi-SichaniPeter K Sorger
Dec 18, 2013·PLoS Computational Biology·Matthias JeschkeStefan Legewie
Dec 22, 2012·Expert Review of Proteomics·Ferdinando MannelloMauro Magnani
Dec 15, 2012·Seminars in Immunology·Rachel A GottschalkRonald N Germain
Nov 15, 2012·Molecular Systems Biology·Jörg SchaberAlejandro Colman-Lerner
Jan 23, 2014·CPT: Pharmacometrics & Systems Pharmacology·M R BirtwistleJ M Gallo
Feb 21, 2013·Molecular Systems Biology·Carlos F LopezPeter K Sorger
Feb 7, 2013·Molecular Systems Biology·Hoda EydgahiPeter K Sorger
Sep 6, 2013·CPT: Pharmacometrics & Systems Pharmacology·D C Kirouac, M D Onsum
Apr 30, 2015·Trends in Cell Biology·Deborah A Flusberg, Peter K Sorger
Oct 19, 2011·Current Opinion in Genetics & Development·Alexander Loewer, Galit Lahav
Jan 21, 2015·Cell Reports·Edward C StitesKodi S Ravichandran
Sep 26, 2017·PLoS Computational Biology·Stefan M KallenbergerDirk-Peter Herten
Jan 28, 2018·Nature Communications·Silvia Márquez-JuradoFrancisco J Iborra
Jan 18, 2019·PLoS Computational Biology·Keesha E EricksonWilliam S Hlavacek
Feb 15, 2015·Molecular Systems Biology·Maxim N ShokhirevAlexander Hoffmann
May 9, 2015·Molecular Systems Biology·Jérémie RouxPeter K Sorger
Jan 27, 2018·Molecular Systems Biology·Jette StrasenAlexander Loewer
May 16, 2018·Molecular Systems Biology·Kyle M KovaryMary N Teruel
Jun 6, 2013·Physical Biology·Deborah A Flusberg, Peter K Sorger
May 14, 2017·Proceedings of the National Academy of Sciences of the United States of America·Ryan SudermanEric J Deeds
May 16, 2018·CPT: Pharmacometrics & Systems Pharmacology·Daniel C Kirouac
Oct 26, 2018·Nature Protocols·Areti TsigkinopoulouRainer Breitling
Nov 14, 2019·BMC Cancer·Manuela SalvucciJochen H M Prehn
Feb 7, 2015·Médecine sciences : M/S·Jérémie RouxPaul Hofman
Sep 1, 2016·Discrete and Continuous Dynamical Systems. Series B·Catherine Ha TaTian Hong
Dec 15, 2020·Molecular Systems Biology·Marie Oliver MetzigAlexander Hoffmann
May 22, 2021·Nature Communications·Jennifer Oyler-YanivRoy Wollman
Sep 26, 2017·Current Opinion in Systems Biology·Jacob Stewart-Ornstein, Galit Lahav

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Methods Mentioned

BETA
flow cytometry
FACS

Software Mentioned

MatLab
custom Perl script
Jacobian
RP
RESgroup
MOMP
EARM
IMS
EARM1

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