The Lxxll Motif of Murine Forkhead Transcription Factor Foxo1 Mediates Sirt1-dependent Transcriptional Activity.
From: Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Disease, Kobe University Graduate School of Medicine, Kobe, Japan. nakaej@med.kobe-u.ac.jp
The Journal of clinical investigation
- Publish Date: Sep 2006
- ISSN: 0021-9738
- Volume: 116
- Issue: 9
- Pages: 2473-83
- Medium: Print
- Language: English
- Citation (JAMA): Nakae Jun, Cao Yongheng, Daitoku Hiroaki, et al. The Lxxll Motif of Murine Forkhead Transcription Factor Foxo1 Mediates Sirt1-dependent Transcriptional Activity.. J. Clin. Invest. Sep 2006;116:2473-83
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 Lepr db/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.
Mesh Headings (Keywords): 1-Methyl-3-isobutylxanthine, Amino Acid Sequence, Animals, Caenorhabditis elegans, Conserved Sequence, Dexamethasone, Drosophila melanogaster, Forkhead Transcription Factors, Insulin, Leptin, Mice, Mutagenesis, Recombinant Proteins, Sirtuins, Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 16917544
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