The hypoxia-inducible factor and tumor progression along the angiogenic pathway

Abstract

The hypoxia-inducible factor (HIF) is a transcription factor that plays a key role in the response of cells to oxygen levels. HIF is a heterodimer of alpha- and beta-subunits where the alpha-subunit is translated constitutively but has a very short half-life under normal oxygen concentrations. Negative regulation of the half-life and activity of the alpha-subunit is dependent on its posttranslational hydroxylation by hydroxylases that are dependent on oxygen for activity. Thus under low oxygen (hypoxic) conditions the hydroxylases are inactive and the alpha-subunit is stable and able to interact with the beta-subunit to bind and induce transcription of target genes. Hypoxic conditions are encountered in development and in disease states such as cancer. Tumors that have outstripped their blood supply become hypoxic and express high levels of HIF. HIF in turn targets genes that induce survival, glycolysis, and angiogenesis, a form of neovascularization, which ensures the tumor with a continued supply of oxygen and nutrients for further growth.