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Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage

Item Type:Article
Title:Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage
Creators Name:Batchelor, E. and Mock, C.S. and Bhan, I. and Loewer, A. and Lahav, G.
Abstract:DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.
Keywords:Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Gamma Rays, Imidazoles, Mathematics, Theoretical Models, Phosphoprotein Phosphatases, Piperazines, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-mdm2, RNA Interference, Signal Transduction, Tumor Cell Line, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Animals
Source:Molecular Cell
Publisher:Cell Press (U.S.A.)
Page Range:277-289
Date:9 May 2008
Official Publication:https://doi.org/10.1016/j.molcel.2008.03.016
PubMed:View item in PubMed

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