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 cell 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 oxidize specific proline residues in HIF alpha 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.
Renal Section, Hammersmith Campus, Imperial College of Science, Technology and Medicine, Du Cane Road, London W12 ONN.
Patrick H
PH
Maxwell
D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008025:Ligases / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011393:Procollagen-Proline Dioxygenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human; D010100:Oxygen