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The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Nakae, Jun Cao, Yongheng Daitoku, Hiroaki Fukamizu, Akiyoshi Ogawa, Wataru Yano, Yoshihiko Hayashi, Yoshitake |
| Copyright Year | 2006 |
| 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.jci.org/articles/view/25518/version/1/pdf/render |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/25000/25518/JCI0625518.pdf |
| PubMed reference number | 16917544v1 |
| Volume Number | 116 |
| Issue Number | 9 |
| Journal | The Journal of clinical investigation |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Alanine Amino Acids Blood Glucose Deacetylase Dinucleoside Phosphates Exclusion FOXO1 gene Gene Expression Regulation Leucine Liver Glycogen Niacin Nicotinamide adenine dinucleotide (NAD) Protein Domain SIRT1 gene TRANSCRIPTION FACTOR Transcription, Genetic db/db Mouse glucose metabolism glucose tolerance leptin receptor resveratrol simian virus |
| Content Type | Text |
| Resource Type | Article |
