The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing.
The heterodimeric transcription factor HIF (hypoxia-inducible factor), consisting of a labile alpha-subunit and a stable beta-subunit, is a master regulator of genes involved in acute or chronic adaptation to low oxygen. Studies performed over the past 5 years revealed that HIFalpha-subunits are enzymatically hydroxylated in an oxygen-dependent manner. Hydroxylation of either of two conserved prolyl residues targets HIFalpha for destruction by a ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein whereas hydroxylation on a C-terminal asparagine affects HIF transactivation function. Pharmacological manipulation of HIF activity might be beneficial in diseases characterized by abnormal tissue oxygenation including myocardial infarction, cerebrovascular disease, and cancer.
Kaelin
William G
WG
Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. William_kaelin@dfci.harvard.edu
D000818:Animals; D006801:Humans; D006900:Hydroxylation; D051793:Hypoxia-Inducible Factor 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen