title: Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system.
abstract: 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 (HIFalpha: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 HIFalpha 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
authors.forename: Joseph
authors.initials: J
authors.lastname: Riss
authors.forename: Olga
authors.initials: O
authors.lastname: Aprelikova
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015687:Cell Hypoxia; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016571:Neural Networks, Computer; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C497396:ARNT protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D010100:Oxygen