Abstract
Oxygen is a crucial molecule for cellular function. When oxygen demand exceeds supply, the oxygen sensing pathway centred on the hypoxia inducible factor (HIF) is switched on and promotes adaptation to hypoxia by up-regulating genes involved in angiogenesis, erythropoiesis and glycolysis. The regulation of HIF is tightly modulated through intricate regulatory mechanisms. Notably, its protein stability is controlled by the oxygen sensing prolyl hydroxylase domain (PHD) enzymes and its transcriptional activity is controlled by the asparaginyl hydroxylase FIH (factor inhibiting HIF-1).To probe the complexity of hypoxia-induced HIF signalling, efforts in mathematical modelling of the pathway have been underway for around a decade. In this paper, we review the existing mathematical models developed to describe and explain specific behaviours of the HIF pathway and how they have contributed new insights into our understanding of the network. Topics for modelling included the switch-like response to decreased oxygen gradient, the role of micro environmental factors, the regulation by FIH and the temporal dynamics of the HIF response. We will also discuss the technical aspects, extent and limitations of these models. Recently, HIF pathway has been implicated in other disease contexts such as hypoxic inflammation and cancer through crosstalking with pathways like NFκB and mTOR. We will examine how future mathematical modelling and simulation of interlinked networks can aid in understanding HIF behaviour in complex pathophysiological situations. Ultimately this would allow the identification of new pharmacological targets in different disease settings.
Highlights
Hypoxia is the cellular stress which occurs when oxygen demand exceeds supply
(1) Identification of the major pathways responsible for a behaviour can be analytically identified by extreme pathway analysis (EPA) instead of the more computationally-demanding numerical integration of a system of ordinary differential equations (ODE); Switch-like behaviour is predicted to originate from the switching of a prolyl hydroxylase domain (PHD)-O2-Von Hippel-Landau (VHL)-dependent hypoxia inducible factor (HIF) degradation pathway in normoxia to an oxygenindependent degradation pathway in hypoxia
When the ratio is lower, the response is delayed but does not attenuate, in close agreement to experimental data in HEK293 cells [51]. Their model assumes that the PHD: HIF synthesis ratio can be controlled by 3 feedback loops: autocrine HIF up-regulation, negative feedback through HIF up-regulation of PHD2 and succinate production inhibition [28]
Summary
Hypoxia is the cellular stress which occurs when oxygen demand exceeds supply. As a homeostatic response to this challenge, several classes of genes are up-regulated, which encode for proteins involved in angiogenesis, erythropoiesis and glycolysis, such as vascular endothelial growth factor, erythropoietin, most of the glycolytic enzymes and glucose transporters [1]. HRE occupancy and/or mRNA expression in response to changes in oxygen concentration (1) Identification of the major pathways responsible for a behaviour can be analytically identified by extreme pathway analysis (EPA) instead of the more computationally-demanding numerical integration of a system of ODEs; Switch-like behaviour is predicted to originate from the switching of a PHD-O2-VHL-dependent HIF degradation pathway in normoxia to an oxygenindependent degradation pathway in hypoxia. The model predicts an unusual role for FIH in regulating the stability of HIF by protecting HIF-1α from non-PHD mediated degradation (Figure 5C) This prediction is further supported by quantitatively analysis of a reduced model containing core interaction module of the HIF network, and closely matches experimental data using an overexpressed HIF-1α with mutated prolyl residues (making it non-hydroxylable by PHD). Their model assumes that the PHD: HIF synthesis ratio can be controlled by 3 feedback loops: autocrine HIF up-regulation, negative feedback through HIF up-regulation of PHD2 and succinate production inhibition [28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
