Enzyme 15‐lipoxygenase 1 promotes hypoxia‐inducible factor 1α turnover and reduces vascular endothelial growth factor expression: implications for angiogenesis. (25th March 2014)

• Record Type: Journal Article
• Authors: Zhong, Hua; Wang, Ruoxiang; Kelavkar, Uddhav; Wang, Christopher Y.; Simons, Jonathan
• Is Part Of: Cancer medicine. Volume 3:Number 3(2014:Jun.)
• Page Start: 514
• Page End: 525
• Publication Date: 2014-03-25
• Subjects: 616.994005
• DOI: 10.1002/cam4.227
• Languages: English
• ISSNs: 2045-7634

Abstract

<abstract abstract-type="main" id="cam4227-abs-0001"> <title>Abstract</title> <p>Hypoxia‐inducible factor 1<italic>α</italic> (HIF‐1<italic>α</italic>) 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‐1<italic>α</italic> ubiquitination and degradation. Altering the level of 15‐LO1 yields inverse changes in HIF‐1<italic>α</italic> and HIF‐1 transcriptional activity, under both normoxia and hypoxia, and even in CoCl₂‐treated cells where HIF‐1<italic>α</italic> has been artificially elevated. The antagonistic effect of 15‐LO1 is mediated by the Pro⁵⁶⁴/hydroxylation/26S proteasome system, while both the enzymatic activity and the intracellular membrane‐binding function of 15‐LO1 appear to contribute to HIF‐1<italic>α</italic> suppression. Our findings provide a novel mechanism for HIF‐1<italic>α</italic> regulation, in which oxygen‐dependent HIF‐1 activity is modulated by an oxygen‐insensitive lipid metabolic enzyme.</p> </abstract>