Send to

Choose Destination
See comment in PubMed Commons below
J Theor Biol. 2009 Jul 21;259(2):304-16. doi: 10.1016/j.jtbi.2009.03.009. Epub 2009 Mar 17.

Gene regulation in response to graded hypoxia: the non-redundant roles of the oxygen sensors PHD and FIH in the HIF pathway.

Author information

Institut de Signalisation, Biologie du Développement et Cancer, UMR CNRS 6543, Université de Nice Sophia Antipolis, Centre Antoine Lacassagne, 06000 Nice, France.


Hypoxia Inducible Factor (HIF), being the master protein involved in adaptation to low pO(2), plays a major role in many physiological and pathological phenomena: development, inflammation, ischemia and cancer. Prolyl hydroxylase (PHD) and factor inhibiting HIF (FIH) are the two oxygen sensors that regulate the HIF pathway. Here we model the regulatory dynamics in an oxygen gradient by a system of differential equations. A part of the work consists in a qualitative analysis, driven independently of the values of the parameters, which explains the non-redundant functional roles of FIH and PHD. In a second part, we use biological experiments to fit the model in a physiologically relevant context and run simulations. Simulation results are confronted with success to independent biological experiments. The combination of biological data and mathematical analysis stresses that FIH is a fine modulator determining whether a given gene should be induced in mildly or in strongly hypoxic areas. Moreover it gives access to other functional predictions that are not directly accessible by pure experiments, for instance the stoichiometry of prolyl-hydroxylation on HIF, and the switch-like properties of the system.


an interactive simulation interface is available at

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center