title: Sirtuin-7 inhibits the activity of hypoxia-inducible factors.
abstract: Hypoxia-inducible factor (HIF) 1 and HIF-2 are heterodimeric proteins composed of an oxygen-regulated HIF-1α or HIF-2α subunit, respectively, and a constitutively expressed HIF-1β subunit, which mediate adaptive transcriptional responses to hypoxia. Here, we report that Sirt7 (sirtuin-7) negatively regulates HIF-1α and HIF-2α protein levels by a mechanism that is independent of prolyl hydroxylation and that does not involve proteasomal or lysosomal degradation. The effect of Sirt7 was maintained in the presence of the sirtuin inhibitor nicotinamide and upon deletion or mutation of its deacetylase domain, indicating a non-catalytic function. Knockdown of Sirt7 led to an increase in HIF-1α and HIF-2α protein levels and an increase in HIF-1 and HIF-2 transcriptional activity. Thus, we identify a novel molecular function of Sirt7 as a negative regulator of HIF signaling.
authors.affiliation: From the Vascular Program, Institute for Cell Engineering,; the McKusick-Nathans Institute of Genetic Medicine.
authors.forename: Maimon E
authors.initials: ME
authors.lastname: Hubbi
authors.affiliation: From the Vascular Program, Institute for Cell Engineering,; the McKusick-Nathans Institute of Genetic Medicine,; the Predoctoral Training Program in Human Genetics,; the Departments of Medicine, Oncology, Pediatrics, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Hu
authors.affiliation: From the Vascular Program, Institute for Cell Engineering,; the Department of Biomedical Engineering, and.
authors.lastname: Kshitiz
authors.affiliation: From the Vascular Program, Institute for Cell Engineering,; the McKusick-Nathans Institute of Genetic Medicine.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: From the Vascular Program, Institute for Cell Engineering,; the McKusick-Nathans Institute of Genetic Medicine,. Electronic address: gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D037761:Sirtuins / Q000378:metabolism*; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046988:Proteasome Endopeptidase Complex; D037761:Sirtuins; D000099162:Endothelial PAS Domain-Containing Protein 1; C510661:SIRT7 protein, human
keywords: Hypoxia; Hypoxia-inducible Factor (HIF); Sirtuins; Transcription