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Vol. 15, Issue 7, 3042-3052, July 2004

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Properties of Switch-like Bioregulatory Networks Studied by Simulation of the Hypoxia Response Control System

Kurt W. Kohn ^* , Joseph Riss , Olga Aprelikova , John N. Weinstein ^*, Yves Pommier ^*, and J. Carl Barrett 

^* Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892

Submitted December 18, 2003; Revised April 8, 2004; Accepted April 13, 2004
Monitoring Editor: Keith Yamamoto

A complex bioregulatory network could be more easily comprehended if its essential function could be described by a small "core" subsystem, and if its response characteristics were switch-like. We tested this proposition by simulation studies of the hypoxia response control network. We hypothesized that a small subsystem governs the basics of the cellular response to hypoxia and that this response has a sharp oxygen-dependent transition. A molecular interaction map of the network was prepared, and an evolutionarily conserved core subsystem was extracted that could control the activity of hypoxia response promoter elements on the basis of oxygen concentration. The core subsystem included the hypoxia-inducible transcription factor (HIF:ARNT heterodimer), proline hydroxylase, and the von Hippel-Lindau protein. Simulation studies showed that the same core subsystem can exhibit switch-like responses both to oxygen level and to HIF synthesis rate, thus suggesting a mechanism for hypoxia response promoter element-dependent responses common to both hypoxia and growth factor signaling. The studies disclosed the mechanism responsible for the sharp transitions. We show how parameter sets giving switch-like behavior can be found and how this type of behavior provides a foundation for quantitative studies in cells.

Corresponding author. E-mail address: kohnk{at}dc37a.nci.nih.gov.

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