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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ma, Lan Levine, Arnold J. Rice, John Jeremy Wagner, John Hu, Wenwei Stolovitzky, Gustavo A. |
| Description | Author Affiliation: Ma L ( IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 40 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Cycle Proteins Metabolism DNA Damage DNA Repair Physiology DNA-Binding Proteins Models, Biological Protein-Serine-Threonine Kinases Signal Transduction Tumor Suppressor Protein P53 Tumor Suppressor Proteins Ataxia Telangiectasia Mutated Proteins Computer Simulation Feedback, Physiological Proto-Oncogene Proteins C-mdm2 Radiation, Ionizing Comparative Study Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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