Attractor Landscape Analysis Reveals Feedback Loops in the p53 Network That Control the Cellular Response to DNA Damage

Sci. Signal.  20 Nov 2012:
Vol. 5, Issue 251, pp. ra83
DOI: 10.1126/scisignal.2003363

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Charting a Deadly Landscape

Signaling pathways exhibit complex regulatory interactions that can make it difficult to predict the outcome of inhibition of components. Choi et al. used a computational approach called attractor landscape analysis to identify how the states of the activity of molecules in the p53 network resulted in specific cellular responses to DNA damage. Conditions that produced a particular type of attractor state, called a cyclic attractor, were associated with pulsatile p53 activity and with the cell entering a state of cell cycle arrest. Furthermore, modeling the combined inhibition of specific components in the pathway suggested a mechanism to enhance the apoptotic response to DNA damage. The p53 dynamics and cellular response of MCF7 cells to the combined treatment verified the computational predictions. Thus, the authors demonstrated the potential application of this method to identify enhanced chemotherapeutic strategies.