Hypoxia

Availability of oxygen is an absolute requirement for all aerobic life. Mechanisms to continuously sense oxygen concentrations and to execute both genetic and physiological programmes to maintain oxygen homeostasis operate from the level of single cells to the level of the whole organism on different scales in both space and time. On a cellular level, hypoxia inducible factor (HIF) is a central to the oxygen-sensing system in all higher organisms. HIF is a heterodimeric transcription factor comprised of a constitutively expressed β-subunit (HIFβ or ARNT) and an α-subunit, the levels of which are regulated by oxygen levels.

HIFα regulation by oxygen is mediated through a set of non-haem, Fe2+ and 2-oxoglutarate-dependent dioxygenases (PHD1-3), which strictly require oxygen as a substrate. If oxygen levels are sufficiently high, the PHDs, predominantly PHD2, hydroxylate HIFα on prolyl-residues. Hydroxylated HIFα strongly interacts with the tumour suppressor pVHL (Van Hippel Lindau protein), an E3 ubiquitin ligase which targets HIFα for degradation. Thus, if oxygen levels are high, HIFα is unstable and rapidly degraded. If oxygen levels become however limiting for the PHD-catalysed hydroxylation of HIFα, unhydroxylated HIFα can accumulate in the cell and binds to HIFβ. The heteromeric complex then triggers a hypoxia-induced transcriptional programme (Figure 1).
A second direct interface between oxygen and HIF activity has also been established. The asparagyl-hydroxylase FIH (factor inhibiting HIF) hydroxylates HIFα on an asparagine residue, which abolishes interaction of HIF with the co-activator CBP/p300, thus suppressing the induction of HIF-CBP/p300 dependent target genes (not shown). Target genes of HIF include, amongst others, glycolytic enzymes, angiogenic factors, as well as factors promoting nutrient- and iron transport. Many of the HIF-induced proteins act to either mediate adaptation to moderate hypoxia, or to alleviate acute hypoxia.
Besides its normal physiological role, the HIF system has a prominent role in carcinogenesis. Limited oxygen and nutrient availability would normally stop the growth of solid tumours, however this limitation can be overcome by activation of the HIF system, which promotes angiogenesis and thus vascularisation of the tumour. In addition, pseudohypoxia, defined as an aberrant activation of the HIF system independently of oxygen levels, is thought to contribute to the development of certain tumours.
We aim to develop a quantitative understanding of the complex hypoxic response by a combined modelling and experimental approaches.