Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Sci Rep. 2017 Apr 18;7:46571. doi: 10.1038/srep46571.

Abstract

Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. To understand design principles underlying such versatile signaling, we analyzed the response of the tumor suppressor p53 to varying levels of DNA damage in hundreds of individual cells and observed a switch between distinct signaling modes characterized by isolated pulses and sustained oscillations of p53 accumulation. Guided by dynamic systems theory we show that this requires an excitable network structure comprising positive feedback and provide experimental evidence for its molecular identity. The resulting data-driven model reproduced all features of measured signaling responses and is sufficient to explain their heterogeneity in individual cells. We present evidence that heterogeneity in the levels of the feedback regulator Wip1 sets cell-specific thresholds for p53 activation, providing means to modulate its response through interacting signaling pathways. Our results demonstrate how excitable signaling networks can provide high specificity, sensitivity and robustness while retaining unique possibilities to adjust their function to the physiology of individual cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • DNA Damage*
  • Humans
  • MCF-7 Cells
  • Models, Biological*
  • Protein Phosphatase 2C / metabolism
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • PPM1D protein, human
  • Protein Phosphatase 2C