Dataset Information

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

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.

SUBMITTER: Batchelor E

PROVIDER: S-EPMC2579769 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Batchelor Eric E Mock Caroline S CS Bhan Irun I Loewer Alexander A Lahav Galit G

Molecular cell 20080501 3

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, an ...[more]

PMID: 18471974

Similar Datasets

Project description:Background: Pulsed high-power microwave (HPM) has many applications and is constantly being researched to expand its uses in the future. As the number of applications grows, the biological effects and safety level of pulsed HPM become a serious issue, requiring further research. Objective: The brain is regarded as the most vulnerable organ to radiation, raising concerns about determining an acceptable level of exposure. The effect of nanosecond pulses and the mechanisms underlying HPM on the brain has not been studied. For the first time, we observed the effect of pulsed 3.5 GHz HPM on brain normal astrocytes and cancer U87 MG cells, as well as the likely mechanisms involved. Methods: To generate 3.5 GHz HPM, an axial virtual cathode oscillator was constructed on pulsed power generator "Chundoong". The cells were directly exposed to HPM (10, 25, 40, and 60) pulses (1 mJ/pulse), with each pulse delivered after 1 min of charging time to evaluate the dose dependent effects. Results: A strong electric field (∼23 kV/cm) of HPM irradiation primarily causes the production of reactive oxygen species (ROS), altering cell viability, mitochondrial activity, and cell death rates in U87 and astrocytes at certain dosages. The ROS generation in response to HPM exposure was primarily responsible for DNA damage and p53 activation. The hazardous dosage of 60 pulses is acknowledged as having damaging effects on brain normal cells. Interestingly, the particular 25 pulses exhibited therapeutic effects on U87 cells via p53, Bax, and Caspase-3 activation. Conclusion: HPM pulses induced apoptosis-related events such as ROS burst and increased oxidative DNA damage at higher dosages in normal cells and specific 25 pulses in cancer U87. These findings are useful to understand the physiological mechanisms driving HPM-induced cell death, as well as the safety threshold range for HPM exposure on normal cells and therapeutic effects on cancer U87. As HPM technology advances, we believe this study is timely and will benefit humanity and future research.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets