Oscillations and variability in the p53 system.
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.
Geva-Zatorsky
Naama
N
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Rosenfeld
Nitzan
N
Itzkovitz
Shalev
S
Milo
Ron
R
Sigal
Alex
A
Dekel
Erez
E
Yarnitzky
Talia
T
Liron
Yuvalal
Y
Polak
Paz
P
Lahav
Galit
G
Alon
Uri
U
D001683:Biological Clocks / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D025461:Feedback, Physiological; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D006801:Humans; D008962:Models, Theoretical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2