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.