Oscillations and variability in the p53 system

Naama Geva-Zatorsky, Nitzan Rosenfeld, Shalev Itzkovitz, Ron Milo, Alex Sigal, Erez Dekel, Talia Yarnitzky, Yuvalal Liron, Paz Polak, Galit Lahav, Uri Alon

Research output: Contribution to journalArticlepeer-review

470 Scopus citations

Abstract

Understanding the dynamics and variability of protein circuitry requires accurate measurements in living cells as well as theoretical models. To address this, we employed one of the best-studied protein circuits in human cells, the negative feedback loop between the tumor suppressor p53 and Mdm2. We measured the dynamics of fluorescently tagged p53 and Mdm2 over several days in individual living cells. We found that isogenic cells in the same environment behaved in highly variable ways following DNA-damaging gamma irradiation: some cells showed undamped oscillations for at least 3 days (more than 10 peaks). The amplitude of the oscillations was much more variable than the period. Sister cells continued to oscillate in a correlated way after cell division, but lost correlation after about 11 h on average. Other cells showed low-frequency fluctuations that did not resemble oscillations. We analyzed different families of mathematical models of the system, including a novel checkpoint mechanism. The models point to the possible source of the variability in the oscillations: low-frequency noise in protein production rates, rather than noise in other parameters such as degradation rates. This study provides a view of the extensive variability of the behavior of a protein circuit in living human cells, both from cell to cell and in the same cell over time.

Original languageEnglish
Article numbermsb4100068
Pages (from-to)13P
JournalMolecular Systems Biology
Volume2
DOIs
StatePublished - 16 May 2006
Externally publishedYes

Keywords

  • Cancer genetics
  • Fluorescence microscopy
  • Quantitative biology
  • Systems biology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)
  • Agricultural and Biological Sciences (all)
  • Applied Mathematics

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