A Plausible Model for the Digital Response of p53 to DNA Damage
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 br...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-10, Vol.102 (40), p.14266-14271 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Ma, Lan Wagner, John Rice, John Jeremy Hu, Wenwei Levine, Arnold J. Stolovitzky, Gustavo A. Austin, Robert H. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.0501352102 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0501352102</identifier><identifier>PMID: 16186499</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Ataxia Telangiectasia Mutated Proteins ; Biological Sciences ; Cell cycle ; Cell Cycle Proteins - metabolism ; Cell lines ; Computer Simulation ; Control loops ; DNA Damage ; DNA repair ; DNA Repair - physiology ; DNA-Binding Proteins - metabolism ; Feedback, Physiological - physiology ; Genes ; Mathematical models ; Modeling ; Models, Biological ; Monomers ; Oscillation ; Oscillators ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Radiation, Ionizing ; Signal Transduction - physiology ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-10, Vol.102 (40), p.14266-14271</ispartof><rights>Copyright 1993/2005 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Oct 4, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c595t-f5dbe8aba47fd27cadbb43ac0a6e3c39ed17a2ab8254eaed930400f8c81e388a3</citedby><cites>FETCH-LOGICAL-c595t-f5dbe8aba47fd27cadbb43ac0a6e3c39ed17a2ab8254eaed930400f8c81e388a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/40.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3376728$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3376728$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16186499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Lan</creatorcontrib><creatorcontrib>Wagner, John</creatorcontrib><creatorcontrib>Rice, John Jeremy</creatorcontrib><creatorcontrib>Hu, Wenwei</creatorcontrib><creatorcontrib>Levine, Arnold J.</creatorcontrib><creatorcontrib>Stolovitzky, Gustavo A.</creatorcontrib><creatorcontrib>Austin, Robert H.</creatorcontrib><title>A Plausible Model for the Digital Response of p53 to DNA Damage</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Biological Sciences</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell lines</subject><subject>Computer Simulation</subject><subject>Control loops</subject><subject>DNA Damage</subject><subject>DNA repair</subject><subject>DNA Repair - physiology</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Feedback, Physiological - physiology</subject><subject>Genes</subject><subject>Mathematical models</subject><subject>Modeling</subject><subject>Models, Biological</subject><subject>Monomers</subject><subject>Oscillation</subject><subject>Oscillators</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Radiation, Ionizing</subject><subject>Signal Transduction - physiology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0Utv1DAUBWALgei0sGaDkMWiEou0fiW2N0WjDi-pPIRgbd0kN9OMPHGwEwT_Ho9m1AE2XXnh7x7Z9xDyjLMLzrS8HAdIF6xkXJaCM_GALDizvKiUZQ_JgjGhC6OEOiGnKW0YY7Y07DE54RU32dgFeb2kXzzMqa890o-hRU-7EOl0i3TVr_sJPP2KaQxDQho6OpaSToGuPi3pCrawxifkUQc-4dPDeUa-v33z7fp9cfP53Yfr5U3RlLaciq5sazRQg9JdK3QDbV0rCQ2DCmUjLbZcg4DaiFIhYGslU4x1pjEcpTEgz8jVPnec6y22DQ5TBO_G2G8h_nYBevfvzdDfunX46bhQQmibA84PATH8mDFNbtunBr2HAcOcXGUqrZQy90KupbXWyAxf_gc3YY5D3oITuRAjDN-hyz1qYkgpYnf3ZM7crkK3q9AdK8wTL_7-6dEfOsuAHsBu8hgnnMqRSlRVJq_uIa6bvZ_w15Tt873dpCnEOyylrrQw8g-9Grhp</recordid><startdate>20051004</startdate><enddate>20051004</enddate><creator>Ma, Lan</creator><creator>Wagner, John</creator><creator>Rice, John Jeremy</creator><creator>Hu, Wenwei</creator><creator>Levine, Arnold J.</creator><creator>Stolovitzky, Gustavo A.</creator><creator>Austin, Robert H.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20051004</creationdate><title>A Plausible Model for the Digital Response of p53 to DNA Damage</title><author>Ma, Lan ; Wagner, John ; Rice, John Jeremy ; Hu, Wenwei ; Levine, Arnold J. ; Stolovitzky, Gustavo A. ; Austin, Robert H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c595t-f5dbe8aba47fd27cadbb43ac0a6e3c39ed17a2ab8254eaed930400f8c81e388a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Biological Sciences</topic><topic>Cell cycle</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell lines</topic><topic>Computer Simulation</topic><topic>Control loops</topic><topic>DNA Damage</topic><topic>DNA repair</topic><topic>DNA Repair - physiology</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Feedback, Physiological - physiology</topic><topic>Genes</topic><topic>Mathematical models</topic><topic>Modeling</topic><topic>Models, Biological</topic><topic>Monomers</topic><topic>Oscillation</topic><topic>Oscillators</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Radiation, Ionizing</topic><topic>Signal Transduction - physiology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Lan</creatorcontrib><creatorcontrib>Wagner, John</creatorcontrib><creatorcontrib>Rice, John Jeremy</creatorcontrib><creatorcontrib>Hu, Wenwei</creatorcontrib><creatorcontrib>Levine, Arnold J.</creatorcontrib><creatorcontrib>Stolovitzky, Gustavo A.</creatorcontrib><creatorcontrib>Austin, Robert H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Lan</au><au>Wagner, John</au><au>Rice, John Jeremy</au><au>Hu, Wenwei</au><au>Levine, Arnold J.</au><au>Stolovitzky, Gustavo A.</au><au>Austin, Robert H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Plausible Model for the Digital Response of p53 to DNA Damage</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2005-10-04</date><risdate>2005</risdate><volume>102</volume><issue>40</issue><spage>14266</spage><epage>14271</epage><pages>14266-14271</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>16186499</pmid><doi>10.1073/pnas.0501352102</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Ataxia Telangiectasia Mutated Proteins Biological Sciences Cell cycle Cell Cycle Proteins - metabolism Cell lines Computer Simulation Control loops DNA Damage DNA repair DNA Repair - physiology DNA-Binding Proteins - metabolism Feedback, Physiological - physiology Genes Mathematical models Modeling Models, Biological Monomers Oscillation Oscillators Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins c-mdm2 - metabolism Radiation, Ionizing Signal Transduction - physiology Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism |
| title | A Plausible Model for the Digital Response of p53 to DNA Damage |
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