2016/03/21 by Sarah E. Wilkins, Martine I. Abboud, Rebecca L. Hancock +1 · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Cancer, Hypoxia, and Metabolism #Adipose Tissue and Metabolism #High Altitude and Hypoxia
paper · pdf · doi:10.1002/cmdc.201600012
openalex publication_date 2016/03/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/15
Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein-protein and protein-nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein-protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.