hypoxia-inducible factor (HIF)
hypoxia-inducible factor (HIF)-1α
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The mechanisms whereby oxygen sensing leads to activation and transcription of EPO are still incompletely understood. Only in recent years, the central role of hypoxia-inducible factor (HIF)-1α has been discovered and involved in this process (for a review, see Ref. 17 and Fig. 5A). HIF-1α is continuously produced, but continuously inactivated by its binding to another protein, Von Hippel Lindau tumor-suppressor protein, and by subsequent ubiquitous metabolization by hydroxylation of proline residues. The configuration changes leading to the binding, and thus destruction of HIF-1α is regulated by a redox mechanism, with glutathione playing a central role. The oxidized form of glutathione, GSSG, which is known to play a major role in the neutralization (scavenging) of oxygen-free radicals (OFR), interacts at least to two possible sites on the HIF-1α molecule, thereby allowing its inactivation (32).
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