The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing

The heterodimeric transcription factor HIF (hypoxia-inducible factor), consisting of a labile a-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 HIF alpha-subunits are enzymatically hydroxylated in an oxygen-dependent manner. Hydroxylation of either of two conserved prolyl residues targets HIF alpha. 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 myocardical infarction, cerebrovascular disease, and cancer. (c) 2005 Elsevier Inc. All rights reserved.