Oxygen sensing and signaling: impact on the regulation of physiologically important genes

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.