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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Daitoku, Hiroaki Hatta, Mitsutoki Aoyama, Hisanori Yoshimochi, Kenji Matsuzaki, Hitomi Fukamizu, Akiyoshi |
| Description | Author Affiliation: Matsuzaki H ( Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.); |
| Abstract | The FOXO family of forkhead transcription factors plays a key role in a variety of biological processes, including metabolism, cell proliferation, and oxidative stress response. We previously reported that Foxo1, a member of the FOXO family, is regulated through reversible acetylation catalyzed by histone acetyltransferase cAMP-response element-binding protein (CREB)-binding protein (CBP) and NAD-dependent histone deacetylase silent information regulator 2, and that the acetylation at Lys-242, Lys-245, and Lys-262 of Foxo1 attenuates its transcriptional activity. However, the molecular mechanism by which acetylation modulates Foxo1 activity remains unknown. Here, we show that the positive charge of these lysines in Foxo1 contributes to its DNA-binding, and acetylation at these residues by CBP attenuates its ability to bind cognate DNA sequence. Remarkably, we also show that acetylation of Foxo1 increases the levels of its phosphorylation at Ser-253 through the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, and this effect was overridden on the acetylation-deficient Foxo1 mutant. Furthermore, in in vitro kinase reactions, the association of wild-type Foxo1 and its target DNA sequence inhibits the protein kinase B-dependent phosphorylation of Foxo1, whereas mutated Foxo1 proteins, which mimic constitutively acetylated states, are efficiently phosphorylated even in the presence of the DNA. These results suggest that acetylation regulates the function of Foxo1 through altering the affinity with the target DNA and the sensitivity for phosphorylation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 32 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA Metabolism Forkhead Transcription Factors Signal Transduction Physiology Acetylation Animals Blotting, Northern Blotting, Western CREB-Binding Protein Chromatin Immunoprecipitation Electrophoretic Mobility Shift Assay Genetics Luciferases Models, Biological Mutation Phosphorylation Protein Binding Sirtuins Tumor Cells, Cultured Comparative Study Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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