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Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation
Yong-Jun Shin1, Brandon Hencey, Steven M Lipkin
1Electrical and Computer Engineering, Cornell University, Ithaca, New York, United States of America.
Plos One
|August 11, 2011
Summary
The p53-MDM2 feedback loop enables sustained p53 oscillations after DNA damage, adapting to synchronize with DNA repair. Overexpression of MDM2 disrupts this adaptive mechanism, impacting cancer.
Area of Science:
- Molecular Biology
- Systems Biology
- Cancer Research
Background:
- The tumor suppressor protein p53 regulates cell cycle and apoptosis.
- Sustained oscillations of p53 levels post-DNA damage are a key area of research.
- The p53-MDM2 negative feedback loop is implicated in p53 oscillations.
Purpose of the Study:
- To investigate the regulatory mechanisms maintaining sustained p53 oscillations after DNA damage.
- To understand how the p53-MDM2 feedback loop dynamics contribute to undamped p53 oscillations.
- To explore the adaptive nature of the p53-MDM2 feedback loop in response to DNA damage.
Main Methods:
- Frequency domain analysis of the p53-MDM2 system.
- Modeling of feedback loop dynamics and cellular responses to DNA damage.
Main Results:
- Sustained p53 oscillations are modulated by DNA repair-related fluctuations, not solely by the p53-MDM2 feedback loop.
- The p53-MDM2 feedback loop adapts by initially filtering noise, then allowing DNA repair signals to modulate p53 oscillations upon damage.
- The feedback loop increases its damping ratio to synchronize p53 oscillations with DNA repair, suppressing inherent oscillation generation.
- MDM2 overexpression, common in cancers, impairs this adaptive response, reducing responsiveness to damage-induced signals.
Conclusions:
- The p53-MDM2 feedback loop exhibits adaptive properties crucial for regulating p53 dynamics post-DNA damage.
- Disruption of this adaptive mechanism by MDM2 overexpression may contribute to cancer development.
- Understanding these dynamics offers insights into p53 regulation and potential therapeutic strategies.
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