Pathway Switching Explains the Sharp Response Characteristic of Hypoxia Response Network

Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively explained. That model consisted of reactions involving 23 molecular species among which the concentrations of HIF and oxygen were linked through a complex set of reactions. In this paper, we analyze this previous model using a combination of mathematical tools to draw out the key components of the network and explain quantitatively how they contribute to the sharp oxygen response. We find that the switch-like behavior is due to pathway-switching wherein HIF degrades rapidly under normoxia in one pathway, while the other pathway accumulates HIF to trigger downstream genes under hypoxia. The analytic technique is potentially useful in studying larger biomedical networks.