Computational Analysis of Dynamical Responses to the Intrinsic Pathway of Programmed Cell Death

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dc.contributorVirginia Techen
dc.contributor.authorZhang, T. L.en
dc.contributor.authorBrazhnik, P.en
dc.contributor.authorTyson, John J.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessed2014-02-05en
dc.date.accessioned2014-02-26T19:10:05Zen
dc.date.available2014-02-26T19:10:05Zen
dc.date.issued2009-07en
dc.description.abstractMulticellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimmunity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible commitment to the response, and a time delay that is inversely proportional to signal strength. Subdividing the intrinsic pathway into three modules (initiator, amplifier, executioner), we use computer simulation and bifurcation theory to attribute signal threshold and time delay to positive feedback in the initiator module and irreversible commitment to positive feedback in the executioner module. The model accounts for the behavior of mutants deficient in various genes and is used to design experiments that would test its basic assumptions. Finally, we apply the model to study p53-induced cellular responses to DNA damage. Cells first undergo cell cycle arrest and DNA repair, and then apoptosis if the damage is beyond repair. The model ascribes this cell-fate transition to a transformation of p53 from "helper" to "killer" forms.en
dc.description.sponsorshipNSF DMS-0342283, PHY05-51164en
dc.description.sponsorshipICTASen
dc.identifier.citationZhang, Tongli; Brazhnik, Paul; Tyson, John J. "Computational Analysis of Dynamical Responses to the Intrinsic Pathway of Programmed Cell Death," Biophysical Journal 97(2), 415-434 (2009); doi: 10.1016/j.bpj.2009.04.053en
dc.identifier.doihttps://doi.org/10.1016/j.bpj.2009.04.053en
dc.identifier.issn0006-3495en
dc.identifier.urihttp://hdl.handle.net/10919/25772en
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0006349509009709en
dc.language.isoen_USen
dc.publisherCELL PRESSen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectx-linked inhibitoren
dc.subjectcytochrome-c releaseen
dc.subjectcaspase activationen
dc.subjectApoptosisen
dc.subjectproteinen
dc.subjectbax translocationen
dc.subjectdna-damageen
dc.subjecte2f-1-induced Apoptosisen
dc.subjectmitochondrial-membraneen
dc.subjectcycle controlen
dc.subjectp53 pathwayen
dc.titleComputational Analysis of Dynamical Responses to the Intrinsic Pathway of Programmed Cell Deathen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden

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