HIF prolyl 4-hydroxylases and their potential as drug targets.
Hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxia-inducible genes involved in the mediation of survival and adaptive responses to insufficient oxygen availability, such as genes involved in hematopoesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumor progression. The stability of the HIFalpha subunit is regulated by oxygen-dependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFalpha to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFalpha. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFalpha escapes degradation and can translocate to the nucleus and form a functional dimer with HIFbeta that triggers the hypoxic response. HIF-P4Hs are considered as promising drug development targets in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, inflammation, diabetes and severe anemias. Studies with HIF-P4H inhibitors in various animal models and ongoing clinical trials support this hypothesis by demonstrating efficacy in many applications.
Myllyharju
Johanna
J
Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland. johanna.myllyharju@oulu.fi
D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein