Fourier analysis and systems identification of the p53 feedback loop

Naama Geva-Zatorsky, Erez Dekel, Eric Batchelor, Galit Lahav, Uri Alon

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

A key circuit in the response of cells to damage is the p53-mdm2 feedback loop. This circuit shows sustained, noisy oscillations in individual human cells following DNA breaks. Here, we apply an engineering approach known as systems identification to quantify the in vivo interactions in the circuit on the basis of accurate measurements of its power spectrum. We obtained oscillation time courses of p53 and Mdm2 protein levels from several hundred cells and analyzed their Fourier spectra. We find characteristic spectra with distinct low-frequency components that are well-described by a third-order linear model with white noise. The model identifies the sign and strength of the known interactions, including a negative feedback loop between p53 and its upstream regulator. It also implies that noise can trigger and maintain the oscillations. The model also captures the power spectra of p53 dynamics without DNA damage. Parameters such as noise amplitudes and protein lifetimes are estimated. This approach employs natural biological noise as a diagnostic that stimulates the system at many frequencies at once. It seems to be a useful way to find the in vivo design of circuits and may be applied to other systems by monitoring their power spectrum in individual cells.

Original languageEnglish (US)
Pages (from-to)13550-13555
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number30
DOIs
StatePublished - Jul 27 2010
Externally publishedYes

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