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- Gregg L. Semenza
- Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
説明
<jats:p>Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O<jats:sub>2</jats:sub>availability. HIFs are heterodimeric proteins composed of an O<jats:sub>2</jats:sub>-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contribute to the pathogenesis of many cancers, particularly the clear cell type of renal cell carcinoma in which loss of function of the von Hippel-Lindau tumor suppressor blocks HIF-2α degradation. A small molecule inhibitor that binds to HIF-2α and blocks dimerization with HIF-1β is in clinical trials for the treatment of renal cell carcinoma. Targeting HIFs for stabilization or inhibition may improve outcomes in diseases that are common causes of mortality in the US population.</jats:p>
収録刊行物
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- Annual Review of Pharmacology and Toxicology
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Annual Review of Pharmacology and Toxicology 59 (1), 379-403, 2019-01-06
Annual Reviews