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Oscillations and variability in the p53 system.

Naama Geva-Zatorsky1, Nitzan Rosenfeld, Shalev Itzkovitz

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Molecular Systems Biology
|June 15, 2006
PubMed
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Cellular protein circuits exhibit significant variability in their behavior. This study reveals that noise in protein production rates, not degradation, drives these dynamic differences in the p53-Mdm2 feedback loop.

Area of Science:

  • Cellular dynamics
  • Systems biology
  • Molecular mechanisms

Background:

  • Understanding protein circuit dynamics is crucial for cell biology.
  • The p53-Mdm2 negative feedback loop is a well-characterized human cellular circuit.
  • Variability in cellular behavior requires investigation through both experimental and theoretical approaches.

Purpose of the Study:

  • To measure and analyze the dynamics of the p53-Mdm2 protein circuit in living human cells.
  • To investigate the sources of variability in protein circuit behavior.
  • To compare experimental observations with mathematical models.

Main Methods:

  • Utilized fluorescently tagged p53 and Mdm2 proteins for live-cell imaging over several days.
  • Applied DNA-damaging gamma irradiation to observe cellular responses.

Related Experiment Videos

  • Developed and analyzed mathematical models, including a novel checkpoint mechanism.

    • Main Results:

    • Observed significant cell-to-cell variability in p53-Mdm2 oscillations following irradiation.
    • Some cells exhibited sustained, undamped oscillations, while others showed low-frequency fluctuations.
    • Oscillation amplitude varied more than period; sister cells lost correlation post-division.
    • Mathematical models suggested protein production rate noise as the primary source of variability.

    Conclusions:

    • The p53-Mdm2 protein circuit displays extensive cell-intrinsic and temporal variability.
    • Low-frequency noise in protein production rates is a likely driver of observed dynamic differences.
    • This variability is a fundamental aspect of protein circuit function in living cells.