title: Enzyme 15-lipoxygenase 1 promotes hypoxia-inducible factor 1α turnover and reduces vascular endothelial growth factor expression: implications for angiogenesis.
abstract: Hypoxia-inducible factor 1α (HIF-1α) is the regulatory subunit of the heterodimeric HIF-1 that plays a critical role in transcriptional regulation of genes in angiogenesis and hypoxic adaptation, while fatty acid metabolism mediated by lipoxygenases has been implicated in a variety of pathogeneses, including cancers. In this study, we report that 15-lipoxygenase 1 (15-LO1), a key member of the lipoxygenase family, promotes HIF-1α ubiquitination and degradation. Altering the level of 15-LO1 yields inverse changes in HIF-1α and HIF-1 transcriptional activity, under both normoxia and hypoxia, and even in CoCl2 -treated cells where HIF-1α has been artificially elevated. The antagonistic effect of 15-LO1 is mediated by the Pro(564) /hydroxylation/26S proteasome system, while both the enzymatic activity and the intracellular membrane-binding function of 15-LO1 appear to contribute to HIF-1α suppression. Our findings provide a novel mechanism for HIF-1α regulation, in which oxygen-dependent HIF-1 activity is modulated by an oxygen-insensitive lipid metabolic enzyme.
authors.affiliation: Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, 30322; Rutgers Cancer Institute of New Jersey and Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, 08901.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Ruoxiang
authors.initials: R
authors.lastname: Wang
authors.forename: Uddhav
authors.initials: U
authors.lastname: Kelavkar
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Simons
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010101:Oxygen Consumption; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D054875:Ubiquitination / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-lipoxygenase 1; HIF-1α; VEGF; hypoxia; ubiquitination