Conservation and Divergence of p53 Oscillation Dynamics across Species

Cell Syst. 2017 Oct 25;5(4):410-417.e4. doi: 10.1016/j.cels.2017.09.012. Epub 2017 Oct 18.


The tumor-suppressing transcription factor p53 is highly conserved at the protein level and plays a key role in the DNA damage response. One important aspect of p53 regulation is its dynamics in response to DNA damage, which include oscillations. Here, we observe that, while the qualitative oscillatory nature of p53 dynamics is conserved across cell lines derived from human, monkey, dog, mouse, and rat, the oscillation period is variable. Specifically, rodent cells exhibit rapid p53 oscillations, whereas dog, monkey, and human cells show slower oscillations. Computational modeling and experiments identify stronger negative feedback between p53 and MDM2 as the driver of faster oscillations in rodents, suggesting that the period of oscillation is a network-level property. In total, our study shows that despite highly conserved signaling, the quantitative features of p53 oscillations can diverge across evolution. We caution that strong amino acid conservation of proteins and transcriptional network similarity do not necessarily imply conservation of time dynamics.

Keywords: evolution; modeling; negative feedback; p53; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • DNA Damage / genetics
  • Dogs
  • Feedback, Physiological / physiology
  • Gene Expression Regulation / genetics
  • Gene Regulatory Networks / genetics
  • Haplorhini
  • Humans
  • MCF-7 Cells
  • Madin Darby Canine Kidney Cells
  • Mice
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Rats
  • Signal Transduction / genetics
  • Tumor Suppressor Protein p53 / genetics*


  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2