Kinases as upstream regulators of the HIF system: their emerging potential as anti-cancer drug targets.
The hypoxia-inducible factor-1 (HIF-1) is a key regulator in the mammalian response to oxygen deficiency under both physiological and pathological conditions such as cancer. A number of studies indicated an association between tumor hypoxia, increased hypoxia-inducible factor (HIF-1alpha) levels and a poor prognosis. The HIF-1alpha regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation. However, HIFalpha-subunits also respond to various growth factors, hormones, or cytokines under non-hypoxic conditions implicating the involvement of different kinase pathways in their regulation thereby increasing the interest in HIF-1alpha as a new drug target. Herein, we review current knowledge about phosphorylation-dependent HIF-1alpha regulation, HIF-1alpha protein-protein interactions and subcellular localization with emphasis on new therapeutic strategies targeting the HIF pathway.
Dimova
Elitsa Y
EY
Fachbereich Chemie, Abteilung Biochemie, Universität Kaiserslautern, Germany. dimova@chemie.uni-kl.de
Michiels
Carine
C
Kietzmann
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D016503:Drug Delivery Systems; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D011379:Prognosis; D011499:Protein Processing, Post-Translational / Q000502:physiology
D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010770:Phosphotransferases