Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity

The hypoxia-inducible factor alpha-subunits (HIF alpha) are key transcription factors in the mammalian response to oxygen deficiency. The HIF alpha regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation and proteasomal degradation. However, HIF alpha-subunits also respond to various growth factors, hormones, or cytokines under normoxia indicating involvement of different kinase pathways in their regulation. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIF alpha regulating kinases are attractive therapeutic targets. Although numerous kinases were reported to regulate HIF alpha indirectly, direct phosphorylation of HIF alpha affects HIF alpha stability, nuclear localization, and transactivity. Herein, we review the role of phosphorylation-dependent HIF alpha regulation with emphasis on protein stability, subcellular localization, and transactivation.