Oxygen mediated gene regulation

Abstract

SUMMARY: Studies of hypoxia‐inducible cis‐acting sequences from the erythropoietin gene have led to the recognition of a widespread transcriptional response to hypoxia based on the activation of a DNA‐binding complex, hypoxia‐inducible factor‐1 (HIF). Genes with functions in cellular energy metabolism, iron metabolism, catecholamine metabolism, vasomotor control and angiogenesis have subsequently been shown to be responsive to HIF, indicating a role in the coordination of oxygen supply and cellular metabolism. Hypoxia‐inducible factor‐1 is a heterodimer of two basic helix–loop–helix proteins of the PAS family, HIF‐1 alpha and HIF‐1 beta, although different isoforms of each subunit are now known to exist. When oxygen tension is lowered, HIF‐alpha subunits dimerize with HIF‐beta and activate gene transcription. Hypoxia‐inducible factor‐1‐mediated gene transcription is regulated predominantly by oxygen‐dependent destruction of HIF‐alpha via the ubiquitin‐proteasome pathway. This destruction is mediated by a ubiquitin E3 ligase complex, in which the von Hippel‐Lindau (VHL) protein (pVHL) recognizes and binds oxygen‐dependent destruction domain(s) in HIF‐alpha subunits. In VHL disease, the destruction of HIF‐alpha is blocked, at least partly explaining the phenotype. The recognition of HIF‐alpha by pVHL in normoxia has recently been shown to be conditional on enzymatic post‐translational hydroxylation of critical prolyl residues. It is hoped that a detailed understanding of these gene regulatory mechanisms may lead to therapeutically useful interventions in the future, for example by up‐regulating HIF activity in ischaemic disease or down‐regulating it in cancer.