Oxygen homeostasis and cancer: insights from a rare disease

Many aspects of physiology and anatomy are precisely adjusted so that the right amount of oxygen reaches cells throughout the body. Hypoxia-inducible factor-1 (HIF-1) is activated by low oxygen tension in all mammalian cells and underpins many aspects of the impressive ability to match oxygen supply and demand. As examples, HIF-1 regulates: . local capillary architecture via angiogenic signalling . red cell production via erythropoietin . cellular metabolism via increased expression of glucose transporters and glycolytic enzymes. HIF-1 is also important in disease, for example in cancer where it is involved in angiogenesis. This review describes how HIF-1 is regulated by oxygen and the central role played by the von Hippel-Lindau tumour suppressor protein. The underlying oxygen sensor is provided by a family of enzymes which oxidise specific proline residues in HIFalpha subunits. Inhibiting these newly discovered enzymes provides a way of activating HIF-1 in the presence of oxygen - an exciting prospect for therapeutic intervention in ischaemic diseases.