title: Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner.
abstract: Hypoxia-inducible factors (HIFs) are stress-responsive transcriptional regulators of cellular and physiological processes involved in oxygen metabolism. Although much is understood about the molecular machinery that confers HIF responsiveness to oxygen, far less is known about HIF isoform-specific mechanisms of regulation, despite the fact that HIF-1 and HIF-2 exhibit distinct biological roles. We recently determined that the stress-responsive genetic regulator sirtuin 1 (Sirt1) selectively augments HIF-2 signaling during hypoxia. However, the mechanism by which Sirt1 maintains activity during hypoxia is unknown. In this report, we demonstrate that Sirt1 gene expression increases in a HIF-dependent manner during hypoxia in Hep3B and in HT1080 cells. Impairment of HIF signaling affects Sirt1 deacetylase activity as decreased HIF-1 signaling results in the appearance of acetylated HIF-2α, which is detected without pharmacological inhibition of Sirt1. We also find that Sirt1 augments HIF-2 mediated, but not HIF-1 mediated, transcriptional activation of the isolated Sirt1 promoter. These data in summary reveal a bidirectional link of HIF and Sirt1 signaling during hypoxia.
authors.affiliation: Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, Texas 75216, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Elhadji M
authors.initials: EM
authors.lastname: Dioum
authors.forename: Richard T
authors.initials: RT
authors.lastname: Hogg
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
mesh_terms: D000107:Acetylation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000096:biosynthesis*; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D056564:Sirtuin 1; D000099162:Endothelial PAS Domain-Containing Protein 1