Therapeutic strategies that target the HIF system

Human cells respond to conditions of limiting oxygen by a switching on a response involving a gene array regulated by the transcription factor hypoxia inducible factor (HIF). This hypoxic response works both to limit the damage of hypoxia and improve oxygen supply to tissues including by upregulating angiogenesis and erythropoiesis. Studies on the molecular mechanism of the HIF system have identified a mechanism by which the HIF system senses changes in oxygen levels. Degradation of the HIF-α subunit by the ubiquitin proteasome pathway is signalled for by oxygenase catalyzed post-translational prolyl-hydroxylation. HIF-α asparaginyl hydroxylation reduces by the transcriptional activity of HIF. The dependence of the HIF hydroxylase on oxygen for catalysis enables an oxygen dependent response. Modulation of the activity of HIF is a potential therapeutic avenue for the treatment of both ischemic disease and cancer. This chapter summarises the molecular components of the HIF system and ongoing therapeutic strategies. © 2008 Springer US