A plausible model for the digital response of p53 to DNA damage. Export

@article{Ma_2005_plausible, abstract = {Recent observations show that the single-cell response of p53 to ionizing radiation (IR) is "digital" in that it is the number of oscillations rather than the amplitude of p53 that shows dependence on the radiation dose. We present a model of this phenomenon. In our model, double-strand break (DSB) sites induced by IR interact with a limiting pool of DNA repair proteins, forming DSB-protein complexes at DNA damage foci. The persisting complexes are sensed by ataxia telangiectasia mutated (ATM), a protein kinase that activates p53 once it is phosphorylated by DNA damage. The ATM-sensing module switches on or off the downstream p53 oscillator, consisting of a feedback loop formed by p53 and its negative regulator, Mdm2. In agreement with experiments, our simulations show that by assuming stochasticity in the initial number of DSBs and the DNA repair process, p53 and Mdm2 exhibit a coordinated oscillatory dynamics upon IR stimulation in single cells, with a stochastic number of oscillations whose mean increases with IR dose. The damped oscillations previously observed in cell populations can be explained as the aggregate behavior of single cells.}, address = {IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598; Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903.}, author = {Ma, Lan and Wagner, John and John and Hu, Wenwei and Levine, Arnold J. J. and Stolovitzky, Gustavo A. A.}, citeulike-article-id = {339716}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0501352102}, citeulike-linkout-1 = {http://www.pnas.org/content/102/40/14266.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/102/40/14266.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/16186499}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=16186499}, citeulike-linkout-5 = {http://dx.doi.org/http://dx.doi.org/10.1073/pnas.0501352102}, citeulike-linkout-6 = {http://dx.doi.org/10.1073/pnas.0501352102}, day = {4}, doi = {10.1073/pnas.0501352102}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {apoptosis, cellcycle, p53}, month = {September}, number = {40}, pages = {14266--14271}, pdf = {ma\_05\_plausible.pdf}, posted-at = {2005-11-22 21:01:11}, priority = {2}, title = {A plausible model for the digital response of p53 to DNA damage.}, url = {http://dx.doi.org/10.1073/pnas.0501352102}, volume = {102}, year = {2005} }

TY - JOUR ID - Ma_2005_plausible L3 - citeulike-article-id:339716 N2 - Recent observations show that the single-cell response of p53 to ionizing radiation (IR) is "digital" in that it is the number of oscillations rather than the amplitude of p53 that shows dependence on the radiation dose. We present a model of this phenomenon. In our model, double-strand break (DSB) sites induced by IR interact with a limiting pool of DNA repair proteins, forming DSB-protein complexes at DNA damage foci. The persisting complexes are sensed by ataxia telangiectasia mutated (ATM), a protein kinase that activates p53 once it is phosphorylated by DNA damage. The ATM-sensing module switches on or off the downstream p53 oscillator, consisting of a feedback loop formed by p53 and its negative regulator, Mdm2. In agreement with experiments, our simulations show that by assuming stochasticity in the initial number of DSBs and the DNA repair process, p53 and Mdm2 exhibit a coordinated oscillatory dynamics upon IR stimulation in single cells, with a stochastic number of oscillations whose mean increases with IR dose. The damped oscillations previously observed in cell populations can be explained as the aggregate behavior of single cells. IS - 40 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 AD - IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598; Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903. EP - 14271 TI - A plausible model for the digital response of p53 to DNA damage. VL - 102 SP - 14266 KW - apoptosis KW - cellcycle KW - p53 AU - Ma, Lan AU - Wagner, John AU - John AU - Hu, Wenwei AU - Levine, Arnold AU - Stolovitzky, Gustavo PY - 2005/September/04/ UR - http://dx.doi.org/10.1073/pnas.0501352102 ER -