Open AccessOscillations and variability in the p53 system
Author(s) -
GevaZatorsky Naama,
Rosenfeld Nitzan,
Itzkovitz Shalev,
Milo Ron,
Sigal Alex,
Dekel Erez,
Yarnitzky Talia,
Liron Yuvalal,
Polak Paz,
Lahav Galit,
Alon Uri
Publication year - 2006
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb4100068
Subject(s) - biology , oscillation (cell signaling) , cell cycle , noise (video) , positive feedback , negative feedback , biological system , cell , dynamics (music) , cell division , protein dynamics , microbiology and biotechnology , physics , genetics , computer science , protein structure , quantum mechanics , voltage , artificial intelligence , acoustics , electrical engineering , image (mathematics) , engineering , biochemistry
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 the oncogene 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 also 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.