Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage

@article{citeulike:2775339, abstract = {Summary 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.}, author = {Batchelor, Eric and Mock, Caroline S. and Bhan, Irun and Loewer, Alexander and Lahav, Galit }, citeulike-article-id = {2775339}, doi = {10.1016/j.molcel.2008.03.016}, journal = {Molecular Cell}, keywords = {dna-damage}, month = {May}, number = {3}, pages = {277--289}, posted-at = {2008-05-09 12:43:34}, priority = {2}, title = {Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage}, url = {http://dx.doi.org/10.1016/j.molcel.2008.03.016}, volume = {30}, year = {2008} }

TY - JOUR ID - citeulike:2775339 L3 - citeulike-article-id:2775339 TI - Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage JF - Molecular Cell VL - 30 IS - 3 SP - 277 EP - 289 N2 - Summary 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. KW - dna-damage AU - Batchelor, Eric AU - Mock, Caroline AU - Bhan, Irun AU - Loewer, Alexander AU - Lahav, Galit PY - 2008/05/09/ UR - http://dx.doi.org/10.1016/j.molcel.2008.03.016 ER -