The Haase laboratory studies the VHL/HIF oxygen sensing pathway and uses conditional gene targeting technology and transgenesis, as well as biochemical and functional genomics approaches to define the specific roles of the von Hippel-Lindau (VHL) tumor suppressor and individual HIF transcription…
more factors in tumorigenesis, acute ischemia and chronic hypoxic injury, as well as erythropoiesis and iron metabolism. Hypoxia-Inducible Factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors, which regulate biological processes that facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive alpha-subunit, HIF-alpha and a constitutively expressed beta-subunit, HIF-beta, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis and other biological processes. Under conditions of normal oxygen tension HIF-alpha is hydroxylated and targeted for rapid proteasomal degradation by the von VHL/E3-ubiquitin ligase. When cells experience hypoxia, HIF-alpha is stabilized and either dimerizes with HIF-beta in the nucleus to form transcriptionally active HIF executing the canonical hypoxia response, or it physically interacts with other non-HIF proteins, enabling convergence of HIF oxygen sensing with other signaling pathways. Since HIF increases the expression of cytoprotective factors and erythropoietin, pharmacologic inhibition of HIF-alpha degradation offers enormous potential for the treatment of acute hypoxic injuries and anemia.
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