Mechanisms That Enhance Sustainability of p53 Pulses

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The tumor suppressor p53 protein shows various dynamic responses depending on the types and extent of cellular stresses. In particular, in response to DNA damage induced by gamma-irradiation, cells generate a series of p53 pulses. Recent research has shown the importance of sustaining repeated p53 pulses for recovery from DNA damage. However, far too little attention has been paid to understanding how cells can sustain p53 pulses given the complexities of genetic heterogeneity and intrinsic noise. Here, we explore potential molecular mechanisms that enhance the sustainability of p53 pulses by developing a new mathematical model of the p53 regulatory system. This model can reproduce many experimental results that describe the dynamics of p53 pulses. By simulating the model both deterministically and stochastically, we found three potential mechanisms that improve the sustainability of p53 pulses: 1) the recently identified positive feedback loop between p53 and Rora allows cells to sustain p53 pulses with high amplitude over a wide range of conditions, 2) intrinsic noise can often prevent the dampening of p53 pulses even after mutations, and 3) coupling of p53 pulses in neighboring cells via cytochrome-c significantly reduces the chance of failure in sustaining p53 pulses in the presence of heterogeneity among cells. Finally, in light of these results, we propose testable experiments that can reveal important mechanisms underlying p53 dynamics.
Publisher
PUBLIC LIBRARY SCIENCE
Issue Date
2013-06
Language
English
Article Type
Article
Keywords

P53-MDM2 FEEDBACK LOOP; MAMMALIAN CIRCADIAN CLOCK; SINGLE NUCLEOTIDE POLYMORPHISM; DNA-DAMAGE RESPONSE; STOCHASTIC SIMULATION; SELECTIVE COMMUNICATION; P53-MEDIATED APOPTOSIS; HUMAN-CELLS; OSCILLATIONS; DYNAMICS

Citation

PLOS ONE, v.8, no.6

ISSN
1932-6203
DOI
10.1371/journal.pone.0065242
URI
http://hdl.handle.net/10203/203042
Appears in Collection
MA-Journal Papers(저널논문)
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