AUTHOR=Kietzmann Thomas , Mennerich Daniela , Dimova Elitsa Y. 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=4

YEAR=2016

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00011

DOI=10.3389/fcell.2016.00011

ISSN=2296-634X

ABSTRACT=<p>The hypoxia-inducible factor α-subunits (HIFα) are key transcription factors in the mammalian response to oxygen deficiency. The HIFα regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation and proteasomal degradation. However, HIF α-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, HIFα regulating kinases are attractive therapeutic targets. Although numerous kinases were reported to regulate HIFα indirectly, direct phosphorylation of HIFα affects HIFα stability, nuclear localization, and transactivity. Herein, we review the role of phosphorylation-dependent HIFα regulation with emphasis on protein stability, subcellular localization, and transactivation.</p>