Low oxygen stimulates the intellect

This Keystone Symposium on Hypoxia and Development, Physiology and Disease took place in Breckenridge, Colorado, USA, between 16 and 21 January 2006, and was organized by M.C. Simon, R.S. Johnson, A. Giaccia and M. Gassmann.![][1] Cells need oxygen for mitochondrial respiration and a wide range of other metabolic processes. It is increasingly being recognized that there are sophisticated mechanisms for monitoring local oxygenation and that these are used to modulate extensive aspects of cellular behaviour. This excellent meeting was held at 9,600 feet where oxygen is 70% of that at sea level; enough to cause breathlessness on exertion and some nasty headaches.A main focus of the meeting was the oxygen‐response pathway that centres on the hypoxia‐inducible factors 1α (HIF‐1α) and 2α (HIF‐2α). As shown in Fig 1, these two transcription factors share extensive sequence homology, modes of regulation and downstream targets, and regulate the expression of more than 60 genes involved in diverse processes that are crucial for the hypoxic response, such as angiogenesis, anaerobic glycolysis and cell survival. HIF consists of two subunits: the hypoxia‐inducible HIF‐α and the constitutively expressed HIF‐β (also known as aryl hydrocarbon receptor nuclear translocator (ARNT)). Our understanding of the central mechanism of oxygen‐dependent accumulation of HIF‐α—although probably far from complete—is substantial, and is the product of fascinating biochemical and genetic studies performed during the past 20 years (Schofield & Ratcliffe, 2004). We now know that the HIF‐α subunit is rapidly degraded under normoxic conditions via proline hydroxylation mediated by at least three oxygen‐dependent prolyl hydroxylases (PHDs). Hydroxylated residues on HIF‐α are recognized and captured by the product of the von Hippel–Lindau (VHL) gene that subsequently promotes the ubiquitylation and proteasomal degradation of the HIF‐α subunit. Under conditions of low oxygen, the PHDs are significantly less active, leading to the stabilization of HIF‐α, … [1]: /embed/graphic-1.gif