Oxygen sensors and angiogenesis.
Local oxygen tension has a profound effect on the vasculature, which compensates vascular insufficiency through the induction of angiogenesis. An important mediator in this process is the hypoxia-inducible factor (HIF) complex, which is activated in hypoxic cells and increases transcription of a broad range of genes including angiogenic growth factors such as VEGF. HIF is primarily regulated through oxygen-dependent proteasomal destruction of the regulatory subunit, HIF-1 alpha or HIF-2 alpha. Regulation is through the modification of specific prolines in HIF- alpha chains which are hydroxylated by a recently identified family of enzymes which require molecular oxygen and 2-oxoglutarate as cosubstrates, and iron as a cofactor. Following modification HIF- alpha chains are captured by a ubiquitin ligase E3 complex containing the von Hippel-Lindau (VHL) tumour suppressor protein. The HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. The PHD-HIF-VHL system provides a range of opportunities for therapeutic manipulation.
Maxwell
Patrick H
PH
Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, OX3 7BN, UK. pmaxwell@hammer.imm.ox.ac.uk
Ratcliffe
Peter J
PJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D017173:Caenorhabditis elegans; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases / Q000378:metabolism; D008322:Mammals; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases; D010100:Oxygen; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human