Blackwell Publishing Journal Backfiles 1879-2005
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.
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