Journal Article

Detecting and responding to hypoxia

Hao Zhu, Tim Jackson and H. Franklin Bunn

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 17, issue suppl_1, pages 3-7
Published in print January 2002 | ISSN: 0931-0509
Published online January 2002 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/17.suppl_1.3
Detecting and responding to hypoxia

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Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia‐inducible transcription factor 1 (HIF‐1). Activation of HIF‐1 by hypoxia depends on rescue of its α‐subunit from oxygen‐dependent degradation in the proteasome, allowing it to form a heterodimer with HIF‐1β. This then translocates to the nucleus. There, HIF‐1 assembles with a highly conserved orphan nuclear receptor, HNF‐4, and a critical transcriptional adaptor, p300. This complex binds to a 3′ enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF‐1 also activates other genes, the cis‐acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide‐insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF‐1α for ubiquitination and degradation.

Keywords: cytochrome b5; cytochrome b5 reductase; erythropoietin; hypoxia; hypoxia‐inducible factor 1; oxygen sensor

Journal Article.  0 words. 

Subjects: Nephrology

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