Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
HIF plays a central role in the transcriptional response to changes in oxygen availability. The PHD family of oxygen-dependent prolyl hydroxylases plays a pivotal role in regulating HIF stability. The biochemical properties of these enzymes make them well suited to act as oxygen sensors. They also respond to other intracellular signals, including reactive oxygen species, nitric oxide, and certain metabolites, that can modulate the hypoxic response. HIF transcriptional activity is further tuned by FIH1-mediated asparagine hydroxylation. HIF affects signaling pathways that influence development, metabolism, inflammation, and integrative physiology. Accordingly, HIF-modulatory drugs are now being developed for diverse diseases.
Kaelin
William G
WG
Howard Hughes Medical Institute, Boston, MA 02115, USA. william_kaelin@dfci.harvard.edu
Ratcliffe
Peter J
PJ
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001216:Asparagine / Q000378:metabolism; D002952:Citric Acid Cycle; D004795:Enzyme Stability; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D051793:Hypoxia-Inducible Factor 1; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; D001216:Asparagine; D007501:Iron; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D011393:Procollagen-Proline Dioxygenase; D001205:Ascorbic Acid; D010100:Oxygen