Nuclear trapping of the forkhead transcription factor FoxO1 via sirt-dependent deacetylation promotes expression of glucogenetic genes

David Frescas, Luca Valenti, Domenico Accili

Research output: Contribution to journalArticlepeer-review

Abstract

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 over-rides 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 photo-bleaching 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.

Original languageEnglish
Pages (from-to)20589-20595
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number21
DOIs
Publication statusPublished - May 27 2005

ASJC Scopus subject areas

  • Biochemistry

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