Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity
Jun Nakae, … , Yoshihiko Yano, Yoshitake Hayashi
Jun Nakae, … , Yoshihiko Yano, Yoshitake Hayashi
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2473-2483. https://doi.org/10.1172/JCI25518.
View: Text | PDF
Research Article Metabolism

The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity

  • Text
  • PDF
Abstract

The forkhead transcription factor FoxO1 has been identified as a negative regulator of insulin/IGF-1 signaling. Its function is inhibited by phosphorylation and nuclear exclusion through a PI3K-dependent pathway. However, the structure/function relationship of FoxO1 has not been elucidated completely. In this study, we carried out mutation analysis of the FoxO1 coactivator–interacting LXXLL motif (amino acids 459–463). Expression of a 3A/LXXAA mutant, in which 3 Akt phosphorylation sites (T24, S253, and S316) and 2 leucine residues in the LXXLL motif (L462 and L463) were replaced by alanine, decreased both Igfbp-1 and G6Pase promoter activity and endogenous Igfbp-1 and G6Pase gene expression in simian virus 40–transformed (SV40-transformed) hepatocytes. Importantly, mutagenesis of the LXXLL motif eliminated FoxO1 interaction with the nicotinamide adenine dinucleotide–dependent (NAD-dependent) deacetylase sirtuin 1 (Sirt1), sustained the acetylated state of FoxO1, and made FoxO1 nicotinamide and resveratrol insensitive, supporting a role for this motif in Sirt1 binding. Furthermore, intravenous administration of adenovirus encoding 3A/LXXAA FoxO1 into Leprdb/db mice decreased fasting blood glucose levels and improved glucose tolerance and was accompanied by reduced G6Pase and Igfbp-1 gene expression and increased hepatic glycogen content. In conclusion, the LXXLL motif of FoxO1 may have an important role for its transcriptional activity and Sirt1 binding and should be a target site for regulation of gene expression of FoxO1 target genes and glucose metabolism in vivo.

Authors

Jun Nakae, Yongheng Cao, Hiroaki Daitoku, Akiyoshi Fukamizu, Wataru Ogawa, Yoshihiko Yano, Yoshitake Hayashi

×

Figure 6

Nicotinamide inhibits FoxO1-dependent induction of a reporter construct under the control of an Igfbp-1 or G6Pase promoter.

Options: View larger image (or click on image) Download as PowerPoint

                  Nicotinamide inhibits FoxO1-dependent induction of a ...
After hepatocytes were transfected with Igfbp-1/(p925GL3) (A) or G6Pase/luciferase reporter gene (PicaGene/human G6Pase promoter-luciferase) (B), cells were infected with indicated adenovirus. phRL-SV40 was used as an internal control of transfection efficiency. After overnight serum deprivation (black bars) and induction with dexamethasone/8-Br-cAMP/ IBMX as described in Methods in the presence (light gray bars) or absence (dark gray bars) of nicotinamide (50 mM), cells were harvested and luciferase activity was measured. *Statistically significant difference between luciferase activity in the absence and in the presence of nicotinamide in cells transfected with each vector. P < 0.005 by 1-way ANOVA. Data represent mean ± SEM from 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts