HIF1-alpha Signaling Pathway

Hypoxia-inducible factor (HIF) 1-alpha is a ubiquitously expressed, master regulator of genes that allow adaptation to hypoxic conditions. Target genes include VEGF, erythropoietin, glycolytic enzymes, glucose transporters, and other factors critical to vascularization, metabolic regulation, cell multiplication and survival. Because hypoxia is a prominent feature of the tumor microenvironment, HIFs have been recognized as potential targets for novel cancer therapeutics. In addition to its role in tumor vascularization, HIF-1 signaling has also been implicated in the pathophysiology of ischemic disease. In wounds, HIF-1 alpha assists in repair of the epithelium through the relocation of keratinocytes. The activity of HIF family proteins is directly governed by cellular oxygen levels. During conditions of normoxia, human HIF-1 alpha is hydroxylated on proline residues 402 and 564, resulting in rapid ubiquitination and subsequent degradation by the proteasome. Under hypoxia however, proline hydroxylation is diminished, resulting in protection of the molecule from degradation.