Sci. STKE, 16 October 2001
Physiology Enzymes that Sense Oxygen
Mammalian cells adapt to a decrease in environmental oxygen (hypoxia) by sending the transcriptional activating complex, hypoxia inducible factor (HIF) into action. In hypoxia, HIF complexes are spared degradation because their interaction with the von Hippel-Lindau tumor suppressor protein (VHL), which acts as a recognition component for the ubiquitin-proteosome pathway, does not occur. Because hydroxylation of specific prolyl residues of HIF is necessary for interaction with VHL, it has been thought that an enzyme that catalyzes this modification may act as an oxygen sensor that regulates HIF activity. Epstein et al. have now verified that such an enzyme does indeed carry out this process in the worm and in mammalian cells. After demonstrating that an HIF-VHL system of hypoxia sensing does exist in the worm, the authors determined that mutations in gene egl-9, which encodes a 2-oxoglutarate-dependent oxygenase, impaired the up-regulation of HIF activity in response to hypoxia. Recombinant EGL-9 stimulated the HIF-VHL interaction in vitro. Mammalian ELG-9 homologs were also identified and named prolyl hydroxylase domain-containing (PHD) proteins. Their expression and activity in cultured human cells were also regulated by oxygen availability.
A. C. R. Epstein, J. M. Gleadle, L. A. McNeill, K. S. Hewitson, J. O'Rourke, D. R. Mole, M. Mukherji, E. Metzen, M. I. Wilson, A. Dhanda, Y.-M. Tian, N. Masson, D. L. Hamilton, P. Jaakkola, R. Barstead, J. Hodgkin, P. H. Maxwell, C. W. Pugh, C. J. Schofield, P. J. Ratcliffe, C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43-54 (2001). [Online Journal]
Citation: Enzymes that Sense Oxygen. Sci. STKE 2001, tw374 (2001).
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