Abstract
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that plays a crucial role in mediating cellular responses to oxygen. Oxygen availability influences multiple steps in HIF activation and recent studies have indicated that at least two steps in this process are governed by a novel mode of signal transduction involving enzymatic hydroxylation of specific amino acid residues in HIF-alpha subunits by a series of 2-oxoglutarate (2-OG)-dependent oxygenases. These enzymes are non-haem iron enzymes that use dioxygen in the hydroxylation reaction and therefore provide a direct link between the availability of molecular oxygen and regulation of HIF. Prolyl hydroxylation regulates proteolytic destruction of HIF-alpha by the von Hippel-Lindau ubiquitin ligase complex, whereas HIF-alpha asparaginyl hydroxylation regulates recruitment of transcriptional coactivators. The involvement of at least two distinct types of 2-OG-dependent oxygenase in oxygen-regulated transcription suggests that these enzymes may be well suited to a role in cellular oxygen sensing.
Highlights
The cellular response to lack of oxygen has attracted particular interest because of its central involvement in medical pathophysiology
Recognition that the hypoxia-inducible factor (HIF)-α–pVHL protein interaction is suppressed by the classical HIF-activating stimuli of cobaltous ions, iron chelation and hypoxia led to a detailed biochemical analysis of this interaction
These studies demonstrated the existence of two interaction sites for pVHL within the HIF-α oxygen-dependent degradation domain (ODD), corresponding to the NODD and CODD subdomains, and showed that interaction is regulated by enzymatic hydroxylation at specific prolyl residues (Ivan et al, 2001; Jaakkola et al, 2001; Masson et al, 2001; Yu et al, 2001)
Summary
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that plays a crucial role in mediating cellular responses to oxygen. Oxygen availability influences multiple steps in HIF activation and recent studies have indicated that at least two steps in this process are governed by a novel mode of signal transduction involving enzymatic hydroxylation of specific amino acid residues in HIF-α subunits by a series of 2-oxoglutarate (2-OG)-dependent oxygenases. These enzymes are non-haem iron enzymes that use dioxygen in the hydroxylation reaction and provide a direct link between the availability of molecular oxygen and regulation of HIF.
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