Abstract
AbstractAnimals must respond efficiently to changes in oxygen levels. This response is achieved via oxygen‐dependent regulation of a heterodimeric hypoxia‐inducible transcription factor (HIF), which enables upregulation of genes that assist in the hypoxic response. Posttranslational hydroxylation of the HIF‐α subunit at either of two conserved prolyl residues enables binding to the von Hippel–Lindau protein elongin C/B complex that targets HIF‐α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C‐terminal transcriptional activation domain of HIF‐α blocks its interaction with the transcriptional coactivator p300. The HIF prolyl and asparaginyl hydroxylases are oxygen dependent; therefore, their regulation of HIF directly links changes in oxygen concentration and the physiological response to hypoxia. The hypoxic response is implicated in a range of disease states, including cancer, ischemia, and heart disease. Manipulation of the HIF system for therapeutic advantage is therefore an area of medicinal interest.
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