title: Evolutionary conserved regulation of HIF-1β by NF-κB.
abstract: Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-α subunit quantities and their associated activity are regulated in a post-translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-α regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-κB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-κB directly regulates HIF-1β mRNA and protein. In addition, we found that NF-κB-mediated changes in HIF-1β result in modulation of HIF-2α protein. HIF-1β overexpression can rescue HIF-2α protein levels following NF-κB depletion. Significantly, NF-κB regulates HIF-1β (tango) and HIF-α (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer.
authors.affiliation: Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: van Uden
authors.forename: Niall S
authors.initials: NS
authors.lastname: Kenneth
authors.forename: Ryan
authors.initials: R
authors.lastname: Webster
authors.forename: H Arno
authors.initials: HA
authors.lastname: Müller
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C497397:Arnt protein, mouse; C109766:tgo protein, Drosophila