Understanding hypoxia signalling in cells--a new therapeutic opportunity?
The possibility that cells possess specific interfaces with molecular oxygen that have a prime function in biological control has long interested biologists. Specific 'oxygen-sensing' mechanisms have been defined in bacteria and yeast, but, until recently, have remained elusive in higher organisms. Studies of hypoxia pathways have now, however, revealed the existence of a series of non-haem Fe(ll) and 2-oxoglutarate-dependent dioxygenases that catalyse oxygen-regulated hydroxylation of specific amino acids in a key transcription factor termed hypoxia-inducible factors (HIFs). These post-translational hydroxylations govern both the proteolytic stability and activity of HIF and therefore the transcription of many hundreds of human genes whose expression changes in accordance with cellular oxygen availability. This paper will review these developments and consider the biological and potential therapeutic implications.