{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T21:59:43Z","timestamp":1768341583705,"version":"3.49.0"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T00:00:00Z","timestamp":1414022400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1003893","type":"journal-article","created":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T20:55:16Z","timestamp":1414097716000},"page":"e1003893","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":53,"title":["Modeling Dynamics of Cell-to-Cell Variability in TRAIL-Induced Apoptosis Explains Fractional Killing and Predicts Reversible Resistance"],"prefix":"10.1371","volume":"10","author":[{"given":"Fran\u00e7ois","family":"Bertaux","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szymon","family":"Stoma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Drasdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory","family":"Batt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2014,10,23]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/1074-7613(95)90057-8","article-title":"Identification and characterization of a new member of the TNF family that induces apoptosis","volume":"3","author":"SR Wiley","year":"1995","journal-title":"Immunity"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/5517","article-title":"Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo","volume":"5","author":"H Walczak","year":"1999","journal-title":"Nat Med"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/nrc2465","article-title":"The TRAIL apoptotic pathway in cancer onset, progression and therapy","volume":"8","author":"RW Johnstone","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/onc.2012.164","article-title":"On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics","volume":"32","author":"LY Dimberg","year":"2013","journal-title":"Oncogene"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1371\/journal.pbio.0060299","article-title":"Modeling a snap-action, variable-delay switch controlling extrinsic cell death","volume":"6","author":"JG Albeck","year":"2008","journal-title":"PLoS Biol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"4304","DOI":"10.1529\/biophysj.106.099606","article-title":"Modeling of the role of a Bax-activation switch in the mitochondrial apoptosis decision","volume":"92","author":"C Chen","year":"2007","journal-title":"Biophys J"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/81208","article-title":"A mathematical model of caspase function in apoptosis","volume":"18","author":"M Fussenegger","year":"2000","journal-title":"Nat Biotechnol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"e120","DOI":"10.1371\/journal.pcbi.0020120","article-title":"Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability","volume":"2","author":"S Legewie","year":"2006","journal-title":"PLoS Comput Biol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/msb.2010.6","article-title":"Dynamics within the CD95 death-inducing signaling complex decide life and death of cells","volume":"6","author":"L Neumann","year":"2010","journal-title":"Molecular Systems Biology"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"4338","DOI":"10.1038\/sj.emboj.7601295","article-title":"Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein","volume":"25","author":"M Rehm","year":"2006","journal-title":"EMBO J"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/1752-0509-5-204","article-title":"Heterogeneity reduces sensitivity of cell death for TNF-stimuli","volume":"5","author":"M Schliemann","year":"2011","journal-title":"BMC Syst Biol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1083\/jcb.200404158","article-title":"Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis","volume":"166","author":"M Bentele","year":"2004","journal-title":"The Journal of Cell Biology"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature08012","article-title":"Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis","volume":"459","author":"SL Spencer","year":"2009","journal-title":"Nature"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1091\/mbc.E12-10-0737","article-title":"Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes","volume":"24","author":"DA Flusberg","year":"2013","journal-title":"Mol Biol Cell"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"035002","DOI":"10.1088\/1478-3975\/10\/3\/035002","article-title":"Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging","volume":"10","author":"DA Flusberg","year":"2013","journal-title":"Phys Biol"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1016\/j.biocel.2007.02.007","article-title":"TRAIL signalling: decisions between life and death","volume":"39","author":"C Falschlehner","year":"2007","journal-title":"Int J Biochem Cell Biol"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S1074-7613(00)80400-8","article-title":"Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway","volume":"7","author":"PM Chaudhary","year":"1997","journal-title":"Immunity"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/cdd.2010.9","article-title":"TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1","volume":"17","author":"JK Son","year":"2010","journal-title":"Cell Death Differ"},{"key":"ref19","first-page":"249","article-title":"TRAIL-induced caspase\/p38 activation is responsible for the increased catalytic and invasive activities of Akt","volume":"38","author":"BK Sun","year":"2011","journal-title":"Int J Oncol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/cdd.2008.187","article-title":"Dynamics of outer mitochondrial membrane permeabilization during apoptosis","volume":"16","author":"M Rehm","year":"2009","journal-title":"Cell Death Differ"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1073\/pnas.94.3.814","article-title":"Stochastic mechanisms in gene expression","volume":"94","author":"HH McAdams","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Raser JM, O'Shea EK (2005) Noise in gene expression: origins, consequences, and control. Science: 2010\u20133.","DOI":"10.1126\/science.1105891"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.cell.2007.01.023","article-title":"Timescales of genetic and epigenetic inheritance","volume":"128","author":"OJ Rando","year":"2007","journal-title":"Cell"},{"key":"ref24","article-title":"Oscillations and variability in the p53 system","author":"N Geva-Zatorsky","year":"2006","journal-title":"Molecular Systems Biology 2"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"e1002482","DOI":"10.1371\/journal.pcbi.1002482","article-title":"Exploring the contextual sensitivity of factors that determine cell-to-cell variability in receptor-mediated apoptosis","volume":"8","author":"S Gaudet","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nature05316","article-title":"Variability and memory of protein levels in human cells","volume":"444","author":"A Sigal","year":"2006","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/msb.2011.85","article-title":"Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis","volume":"7","author":"BB Aldridge","year":"2011","journal-title":"Molecular Systems Biology"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"e1003056","DOI":"10.1371\/journal.pcbi.1003056","article-title":"STL-based analysis of TRAIL-induced apoptosis challenges the notion of type I\/type II cell line classification","volume":"9","author":"S Stoma","year":"2013","journal-title":"PLoS Comput Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1073\/pnas.0403350102","article-title":"Noisy signal amplification in ultrasensitive signal transduction","volume":"102","author":"T Shibata","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1073\/pnas.0708708105","article-title":"Intrinsic noise, dissipation cost, and robustness of cellular networks: the underlying energy landscape of MAPK signal transduction","volume":"105","author":"S Lapidus","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nature09145","article-title":"Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing","volume":"466","author":"S Tay","year":"2010","journal-title":"Nature"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1186\/1471-2105-8-376","article-title":"Single TNFalpha trimers mediating NF-kappaB activation: Stochastic robustness of NF-kappaB signaling","volume":"8","author":"T Lipniacki","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1529\/biophysj.104.056754","article-title":"Stochastic regulation in early immune response","volume":"90","author":"T Lipniacki","year":"2006","journal-title":"Biophys J"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/msb.2012.38","article-title":"Dynamics of protein noise can distinguish between alternate sources of gene-expression variability","volume":"8","author":"A Singh","year":"2012","journal-title":"Molecular Systems Biology"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1371\/journal.pbio.0040309","article-title":"Stochastic mRNA synthesis in mammalian cells","volume":"4","author":"A Raj","year":"2006","journal-title":"PLoS Biol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1126\/science.1198817","article-title":"Mammalian genes are transcribed with widely different bursting kinetics","volume":"332","author":"DM Suter","year":"2011","journal-title":"Science"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"17454","DOI":"10.1073\/pnas.1213530109","article-title":"Transcriptional burst frequency and burst size are equally modulated across the human genome","volume":"109","author":"RD Dar","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1741-7007-11-15","article-title":"Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods between transcriptional bursts","volume":"11","author":"J Vi\u00f1uelas","year":"2013","journal-title":"BMC Biology"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1007\/s11538-006-9176-7","article-title":"Modeling stochasticity in gene regulation: characterization in the terms of the underlying distribution function","volume":"69","author":"P Paszek","year":"2007","journal-title":"Bull Math Biol"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/msb.2009.75","article-title":"Listening to the noise: random fluctuations reveal gene network parameters","volume":"5","author":"B Munsky","year":"2009","journal-title":"Molecular Systems Biology"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"e1003596","DOI":"10.1371\/journal.pcbi.1003596","article-title":"A Computational Framework for Analyzing Stochasticity in Gene Expression","volume":"10","author":"MS Sherman","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1101\/gad.1093903","article-title":"Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation","volume":"17","author":"D Nijhawan","year":"2003","journal-title":"Genes Dev"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"27345","DOI":"10.1074\/jbc.M504019200","article-title":"Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail","volume":"280","author":"M Poukkula","year":"2005","journal-title":"J Biol Chem"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"14402","DOI":"10.1074\/jbc.M111.304378","article-title":"Proteasome Inhibition Can Impair Caspase-8 Activation upon Submaximal Stimulation of Apoptotic Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) Signaling","volume":"287","author":"MA Laussmann","year":"2012","journal-title":"Journal of Biological Chemistry"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.cell.2011.07.026","article-title":"Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells","volume":"146","author":"PB Gupta","year":"2011","journal-title":"Cell"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1158\/1541-7786.MCR-05-0231","article-title":"Constitutively activated nuclear factor-kappaB, but not induced NF-kappaB, leads to TRAIL resistance by up-regulation of X-linked inhibitor of apoptosis protein in human cancer cells","volume":"4","author":"SJ Braeuer","year":"2006","journal-title":"Mol Cancer Res"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"e19679","DOI":"10.1371\/journal.pone.0019679","article-title":"TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT","volume":"6","author":"N Lalaoui","year":"2011","journal-title":"PLoS ONE"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/cdd.2013.179","article-title":"Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1","volume":"21","author":"J Lemke","year":"2014","journal-title":"Cell Death Differ"},{"key":"ref49","doi-asserted-by":"crossref","unstructured":"Shirley S, Micheau O (2013) Targeting c-FLIP in cancer. Cancer letters. 141\u201350.","DOI":"10.1016\/j.canlet.2010.10.009"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.molcel.2012.05.004","article-title":"A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death","volume":"47","author":"LS Dickens","year":"2012","journal-title":"Molecular Cell"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.molcel.2012.05.006","article-title":"Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model","volume":"47","author":"K Schleich","year":"2012","journal-title":"Molecular Cell"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"20563","DOI":"10.1073\/pnas.1312310110","article-title":"Stimulus-induced modulation of transcriptional bursting in a single mammalian gene","volume":"110","author":"N Molina","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1126\/science.1231456","article-title":"Systematic Identification of Signal-Activated Stochastic Gene Regulation","volume":"339","author":"G Neuert","year":"2013","journal-title":"Science"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1158\/0008-5472.CAN-12-2269","article-title":"Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy","volume":"73","author":"AU Lindner","year":"2013","journal-title":"Cancer Res"}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003893","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T20:03:38Z","timestamp":1588968218000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1003893"}},"subtitle":[],"editor":[{"given":"Jeffrey J.","family":"Saucerman","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,10,23]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1003893","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,23]]}}}