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

被引:277
作者
Ma, L
Wagner, J
Rice, JJ
Hu, WW
Levine, AJ
Stolovitzky, GA
机构
[1] IBM Corp, Thomas J Watson Res Ctr, Funct Genom & Syst Biol Grp, Yorktown Hts, NY 10598 USA
[2] Univ Med & Dent New Jersey, Canc Inst New Jersey, New Brunswick, NJ 08903 USA
[3] Inst Adv Study, Sch Nat Sci, Princeton, NJ 08540 USA
关键词
DNA damage response; mathematical model of p53; p53; regulation; pathway;
D O I
10.1073/pnas.0501352102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:14266 / 14271
页数:6
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