The subtle side to hypoxia inducible factor (HIFα) regulation

The transcription factor hypoxia inducible factor α‐subunit (HIFα) is pivotal in the cellular response to the stress of hypoxia. Post‐translational modification of HIFα by hydroxylase enzymes has recently been identified as a key ‘oxygen sensing’ mechanism within the cell. The absence of the substrate oxygen prevents the hydroxylases from modifying HIFα during hypoxia and allows dramatic up‐regulation of both HIFα protein stability and transcriptional activation capability. In addition to this oxygen‐dependent response, increased HIFα protein levels and/or enhanced transcriptional activity during normoxic conditions can be stimulated by various receptor‐mediated factors such as growth‐factors and cytokines (insulin, insulin‐like growth factor 1 or 2, endothelial growth factor, tumour necrosis factor α, angiotensin‐2). Oncogenes are also capable of HIFα activation. This induction is generally less intense than that stimulated by hypoxia and although not fully elucidated, appears to occur via hypoxia‐independent, receptor‐mediated signal pathways involving either phosphatidyl‐inositol‐3‐kinase/Akt or mitogen activated protein kinase (MAPK) pathways, depending on the cell‐type. Activation of Akt increases HIFα protein synthesis in the cell and results in increased HIFα protein and transcriptional activity. MAPK also activates HIFα protein synthesis and additionally may potentiate HIF1α transcriptional activity via a separate mechanism that does not necessarily require protein stabilization. Here we review the mechanisms and function of receptor‐mediated signals in the multifaceted regulation of HIFα.