Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers

Abstract:  Oxygen is essential for aerobic metabolism in all mammalian cells. To maintain function and homeostasis, cells have to be able to sense and respond to inadequate oxygen levels (hypoxia). A family of transcription factors called hypoxia-inducible factors (HIFs) plays a central role in orchestrating the cellular response to hypoxia. HIF-1, the first member of the family, is a heterodimeric protein consisting of a constitutively expressed subunit, HIF-1β, and an oxygen-sensitive inducible subunit, HIF-1α. HIF-1α protein is usually degraded under normal oxygen concentrations (normoxia), but in hypoxic conditions or in the presence of iron chelators, the degradation rate decreases, and HIF-1α protein accumulates and associates with HIF-1β to form a functional transcription complex, triggering the transcription of a host of hypoxia-inducible genes. Recent studies have shed light on the mechanisms of hypoxia-driven stabilization of HIF-1α protein. Under normal oxygen tension, HIF-1α protein is hydroxylated on two proline residues by a family of oxygen-dependent prolyl hydroxylases (PHD1–3), and the modified HIF-1α becomes a substrate for polyubiquitination by a protein complex containing von Hippel-Lindau proteins (pVHL) and is thus targeted for degradation. The enzymatic activities of PHD proteins are sensitive to oxygen availability. Under low-oxygen conditions, PHD proteins are unable to modify the HIF-1α protein, keeping HIF-1α protein unhydroxylated and allowing it to escape pVHL recognition and subsequent degradation, resulting in the triggering of the hypoxia responses. Citati on: Chi J-T, Wang Z, Nuyten DSA, Rodriguez EH, Schaner ME, et al. (2006) Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers. PLoS Med 3(3): e47. doi:10.1371/journal. pmed.0030047