This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the main ways animals respond to low oxygen concentration is through an alpha/beta heterodimer transcription factor, hypoxia inducible factor (HIF). During hypoxia, HIF binds to response elements linked to an array of genes associated with hypoxia including, in humans, those associated with angiogenesis (VEGF) and erythropoiesis (erythropoietin, EPO). Levels of the alpha subunit of HIF are low under normoxic conditions and increase under hypoxic conditions. The post-translational enzymatic hydroxylation of proline at either of two sites, targets HIF-alpha to the von Hipple Lindau protein (pVHL), which in turn recruits a ubiquitin ligase enabling HIF-alpha's proteasomal degradation. Regulation of HIF-alpha levels and its transcriptional activity are mediated by prolyl hydoxylase isozymes PHD1,2,and 3 and an asparaginyl hydroxylase, factor inhibiting HIF (FIH), both of which utilize molecular oxygen and 2-oxoglutarate (2OG) as substrates and thus act as direct oxygen level sensors. Both types of hydroxylases belong to the 2-OG dependent non-haem iron dioxygenase family of enzymes. There is great therapuetic potential through the modulation of transcription factors using small molecules and/or peptides. Specific inhibition of the HIF hydroxylases may not only provide a useful means of initiating angiogenesis, but may also provide valuable information on the poorly understood functional roles of the individual hydroxylases in cell signaling.
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