A growing number of physiologically relevant genes are regulated in respons
e to changes in intracellular oxygen tension. It is likely that cells from
a wide variety of tissues share a common mechanism of oxygen sensing and si
gnal transduction leading to the activation of the transcription factor hyp
oxia-inducible factor 1 (HIF-1). Besides hypoxia, transition metals (Co2+,
Ni2+ and Mn2+) and iron chelation also promote activation of HIF-1. Inducti
on of HIF-1 by hypoxia is blocked by the heme ligands carbon monoxide and n
itric oxide. There is growing, albeit indirect, evidence that the oxygen se
nsor is a flavoheme protein and that the signal transduction pathway involv
es changes in the level of intracellular reactive oxygen intermediates. The
activation of HIF-1 by hypoxia depends upon signaling-dependent rescue of
its a-subunit from oxygen-dependent degradation in the proteasome, allowing
it to form a heterodimer with HIF-1 beta (ARNT), which then translocates t
o the nucleus and impacts on the transcription of genes whose cis-acting el
ements contain cognate hypoxia response elements. (C) 1999 Elsevier Science
B.V. All rights reserved.