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Oxygen availability regulates many physiological and pathophysiological processes, including embryonic development, high-altitude adaptation, wound healing, and inflammation, as well as contributing to the pathophysiology of ischemic diseases and cancer. Central to our understanding of these processes is an elucidation of the molecular mechanisms by which cells react and adapt to insufficient oxygen supply (hypoxia). The last few years have brought a wealth of novel insights into these processes. Oxygen-sensing protein hydroxylases have been discovered that regulate the abundance and activity of three hypoxia-inducible transcription factors (HIFs) and thereby the activity of at least 70 effector genes involved in hypoxic adaptation. In addition to the increase in HIF abundance in response to a decrease in tissue oxygenation, it became evident that HIF abundance is also proactively increased, even under normoxic conditions, in response to stimuli that lead to cell growth and thus ultimately require higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli–activated signaling pathways that influence the abundance and activity of HIFs include pathways that involve the activation of kinases and liberation of reactive oxygen species. All of these pathways converge at the hypoxia-response elements (HREs) of effector genes, to which the HIFs bind, thereby enabling HIF-dependent induction of gene expression.
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