Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death. Export

@article{citeulike:6083586, abstract = {Multicellular 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.}, author = {Zhang, Tongli and Brazhnik, Paul and Tyson, John J.}, citeulike-article-id = {6083586}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.bpj.2009.04.053}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19619456}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19619456}, day = {22}, doi = {10.1016/j.bpj.2009.04.053}, issn = {1542-0086}, journal = {Biophysical journal}, keywords = {p53}, month = {July}, number = {2}, pages = {415--434}, posted-at = {2009-11-08 01:38:09}, priority = {0}, title = {Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.}, url = {http://dx.doi.org/10.1016/j.bpj.2009.04.053}, volume = {97}, year = {2009} }

TY - JOUR ID - citeulike:6083586 L3 - citeulike-article-id:6083586 N2 - Multicellular 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. IS - 2 JF - Biophysical journal SN - 1542-0086 EP - 434 TI - Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death. VL - 97 SP - 415 KW - p53 AU - Zhang, Tongli AU - Brazhnik, Paul AU - Tyson, John PY - 2009/07/22/ UR - http://dx.doi.org/10.1016/j.bpj.2009.04.053 ER -