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Semin Cell Dev Biol. 2002 Feb;13(1):29-37.

Oxygen sensors and angiogenesis.

Author information

1
Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, OX3 7BN, UK. pmaxwell@hammer.imm.ox.ac.uk

Abstract

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.

PMID:
11969369
DOI:
10.1006/scdb.2001.0287
[Indexed for MEDLINE]

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