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


BACKGROUND
an interactive simulation interface is available at http://sdi.ljad.free.fr/spip.php?article111.
Dayan
Frédéric
F
Institut de Signalisation, Biologie du Développement et Cancer, UMR CNRS 6543, Université de Nice Sophia Antipolis, Centre Antoine Lacassagne, 06000 Nice, France. Frederic.Dayan@unice.fr
Monticelli
Marc
M
Pouysségur
Jacques
J
Pécou
Elisabeth
E
D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D006899:Mixed Function Oxygenases; D008954:Models, Biological; D010100:Oxygen / Q000008:administration & dosage; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D051793:Hypoxia-Inducible Factor 1; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen