HIF, being the master protein involved in adaptation to low p[O2 ], plays a ma jor role in many physiological and pathological phenomena : development, inflammation, ischemia and cancer. PHD and 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 stoechiometry of prolyl-hydroxylation on HIF, and the switch-like properties of the system.

The following simulation interface uses a "Flash-subset" of the software "xdim" which is an interactive device for dynamical systems, freely available upon request (send mail to marc.monticelli at unice.fr). The dynamical equations, the equations at equilibrium and parameter values are taken from the article.

The curves show the evolution of the equilibrium value as Oxygen is varied. Two variables are chosen : the total HIF protein, and the gene stimulation function. In the following, the equilibrium equations are simulated. Those equations are valid only for non zero parameters.