The subtle side to hypoxia inducible factor (HIFα) regulation

Rebecca L. Bilton, Grant W. Booker

Research output: Contribution to journalReview articlepeer-review

144 Citations (Scopus)


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 H IFα protein synthesis in the cell and results in increased HIFα protein and transcriptional activity. MAPK also activates HIFα protein synthesis and additionally may potentiate HIFα 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.

Original languageEnglish
Pages (from-to)791-798
Number of pages8
JournalEuropean Journal of Biochemistry
Issue number5
Publication statusPublished - Mar 2003
Externally publishedYes


  • Growth factor
  • HIFα
  • MAPK
  • Oncogene
  • PI3K


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