Oxygen sensors and angiogenesis.

Journal article

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.

Authors: Maxwell, P; Ratcliffe, P

• Publication status: Published
• Journal: Seminars in cell and developmental biology
• Volume: 13
• Issue: 1
• Pages: 29-37
• Publication date: 2002-02-01
• DOI: 10.1006/scdb.2001.0287
• EISSN: 1096-3634
• ISSN: 1084-9521
• Language: English
• Keywords: Trans-Activators; Basic Helix-Loop-Helix Transcription Factors; Humans; Animals; von Hippel-Lindau Disease; Ligases; Mammals; Hypoxia-Inducible Factor 1, alpha Subunit; Ubiquitin-Protein Ligases; Caenorhabditis elegans; Oxygen; Transcription Factors; Von Hippel-Lindau Tumor Suppressor Protein; Neovascularization, Physiologic; Tumor Suppressor Proteins