Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.
Activation of NAD-dependent deacetylases, or Sirtuins, prolongs life span and mimics the effects of caloric restriction in yeast. The FoxO subfamily of forkhead transcription factors has been shown to mediate some of the effects of Sirtuins. Here we have shown that Sirtuin activation or hydrogen peroxide treatment overrides the phosphorylation-dependent nuclear exclusion of FoxO1 caused by growth factors and causes nuclear translocation of FoxO1 in hepatocytes. Kinetic measurements of nuclear fluorescence recovery after photobleaching show that FoxO1 is readily diffusible within the nucleus under normal conditions but becomes restricted within a nuclear subdomain following treatment with the prototypical Sirtuin agonist resveratrol or oxidative stress. Expression of FoxO1 target genes is accordingly increased, leading to activation of gluconeogenesis and increased glucose release from hepatocytes. Selective modulation of the FoxO/Sirtuin interaction represents a promising therapeutic modality for metabolic disorders.
Frescas
David
D
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032.
Valenti
Luca
L
Accili
Domenico
D
D000107:Acetylation; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018384:Oxidative Stress; D010766:Phosphorylation; D038761:Photobleaching; D011993:Recombinant Fusion Proteins; D000077185:Resveratrol; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D011993:Recombinant Fusion Proteins; D013267:Stilbenes; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D037761:Sirtuins; D005947:Glucose; D000077185:Resveratrol