HIF Prolyl 4-Hydroxylases and their Potential as Drug Targets
Affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, P. O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland.
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 HIFα subunit is regulated by oxygendependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFα to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFα. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFα escapes degradation and can translocate to the nucleus and form a functional dimer with HIFβ 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.
Keywords: Hypoxia response, hypoxia-inducible transcription factor, 2-oxoglutarate dioxygenase, prolyl 4-hydroxylase, ischemia, anemia
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