Hypoxia-inducible Factor (HIF) in Hormone Signaling During Health and Disease

Nathalie      Dehne; Dominik      Fuhrmann; Bernhard      Brune

Abstract

Hypoxia-inducible factor (HIF) is a dimeric transcription factor identified as the major regulator of hypoxic responses in cells. Its activity is mainly regulated by protein stability. In well-oxygenated tissues prolyl hydroxylases hydroxylate HIF-1α and HIF-2α protein to provoke their proteasomal degradation. Under hypoxia the α-subunits are stabilized and dimerize with ß-subunits to constitute active transcriptional complexes. As the α-subunits are constantly translated and degraded, any interference with cellular translation will alter HIF-α expression and HIF activity. Cytokines such as interleukins or interferons as well as growth factors such as vascular endothelial growth factor or insulin-like growth factor are good examples of hormones that affect transcription, translation, or degradation of HIF-1α. In turn, HIF specific target genes also modulate the expression and/or signaling quality of cytokines or growth factors to create signal amplifying/intercepting cellular networks. We define how these signaling circuits promote or delay the progression of diseases and describe potential outcomes for patients.

Keywords: Hypoxia-inducible factor, cancer, insulin, insulin-like growth factor, interferon, interleukin, mTOR, tumor necrosis factor, vascular endothelial growth factor.