Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1.
To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinately increase production of protective factors. Hypoxia changes cellular metabolism and thus activates redox-sensitive as well as oxygen-dependent signal transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing deacetylase, selectively stimulates activity of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2alpha) during hypoxia. The effect of Sirt1 on HIF-2alpha required direct interaction of the proteins and intact deacetylase activity of Sirt1. Select lysine residues in HIF-2alpha that are acetylated during hypoxia confer repression of Sirt1 augmentation by small-molecule inhibitors. In cultured cells and mice, decreasing or increasing Sirt1 activity or levels affected expression of the HIF-2alpha target gene erythropoietin accordingly. Thus, Sirt1 promotes HIF-2 signaling during hypoxia and likely other environmental stresses.
Dioum
Elhadji M
EM
Veterans Affairs North Texas Health Care System, Department of Medicine, 4500 South Lancaster Road, Dallas, TX 75216, USA.
Chen
Rui
R
Alexander
Matthew S
MS
Zhang
Quiyang
Q
Hogg
Richard T
RT
Gerard
Robert D
RD
Garcia
Joseph A
JA
D000107:Acetylation; D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D050505:Mutant Proteins; D056564:Sirtuin 1; D037761:Sirtuins; D000099162:Endothelial PAS Domain-Containing Protein 1; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse