Editors' ChoiceSystems Biology

Oscillator Fine-Tuning

Science Signaling  12 Oct 2010:
Vol. 3, Issue 143, pp. ec315
DOI: 10.1126/scisignal.3143ec315

Impressive progress is being made in understanding biological regulatory networks and the feedback structures they use. Similarly, functioning synthetic molecular machines like oscillators have been built. But the ultimate goal is to enable control of biological regulatory circuits within cells, both to understand how they work and to provide new therapeutic strategies. Toettcher et al. set out to explore such manipulation of a simplified version of the signaling pathway controlled by the tumor suppressor protein p53. In a human breast cancer–derived cell line, the authors could stimulate production of p53 from an inducible promoter, which initiated feedback through increased synthesis of endogenous Mdm2, the ubiquitin ligase that enhances degradation of p53. Just these components were enough to generate typical oscillations in the abundance of p53 like those that occur when p53 is activated in cells with DNA damage. Toettcher et al. used a combination of mathematical modeling and experimental manipulation of the cells to show that they could independently alter the amplitude of oscillations in transcription of p53, the damping of the oscillations (whether the amplitude of successive oscillations decreases over time), or the frequency of the oscillations. Controlling the rate of transcription of p53 by altering the promoter tuned just the amplitude of the oscillations. Modeling predicted that the damping of the oscillation could be controlled by additional positive or negative feedback loops. Indeed, manipulation of the transcription factor that controlled the inducible promoter to add positive or negative feedback decreased or increased, respectively, the damping of the oscillations. The frequency of oscillations in p53 in cells responding to DNA damage is constant regardless of the strength of the stimulus. However, the authors’ model showed that it should be possible to modulate the frequency by altering the affinity of the interaction between p53 and Mdm2. This effect was confirmed in experiments with a pharmacological agent that altered the interaction. Toettcher et al. point out that this sort of manipulation in cells can be used to help determine the function of particular dynamic properties of p53 signaling and other oscillatory cellular regulatory circuits. Furthermore, it can, in theory, be applied to restore proper function in signaling networks deranged by disease processes.

J. E. Toettcher, C. Mock, E. Batchelor, A. Loewer, G. Lahav, A synthetic–natural hybrid oscillator in human cells. Proc. Natl. Acad. Sci. U.S.A. 107, 17047–17052 (2010). [Abstract] [Full Text]