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Fig. 3. Regulation of FoxO proteins in response to external and internal stimuli. Treatment of cells with growth factors such as IGF-1 and insulin leads to the activation of Akt (A) and CDK2 (B) through the Ras- and PI3K-dependent pathways. This in turn results in hyperphosphorylation of FoxO transcription factor. Akt-mediated phosphorylation allows FoxO proteins to bind to the chaperone proteins 14-3-3 and be exported into the cytoplasm in a CRM1-dependent manner. The substrate-binding F-box protein Skp2 of the SCFSkp2 E3 ligase also interacts with and ubiquitylates FoxO1 (C). This interaction requires Akt-mediated phosphorylation of FoxO1 at serine 256. CDK2-mediated phosphorylation of FoxO1 also leads to cytoplasmic localization of FOXO1 through a mechanism that appears not to be affected by 14-3-3 binding. Upon DNA damage, however, CDK2-dependent phosphorylation and cytoplasmic localization of FoxO1 is abolished; this depends on activation of Chk1 and Chk2 (D). Similarly, FoxO proteins translocate to the nucleus in response to oxidative stress. Oxidative-stress-promoted nuclear localization of FoxO proteins is likely to be because of their phosphorylation by JNK (E), JNK-dependent phosphorylation of 14-3-3 proteins (F) or direct phosphorylation of FoxO proteins by MST1 (G). Oxidative stress also enhances the interaction of FoxO proteins with 
-catenin and thus their activity (H). Expression of the histone acetyl-transferases CBP and p300 has been shown to enhance the transcriptional activity of FoxO proteins. Interestingly, it has been shown that FoxO1 can be acetylated by CBP at three lysine residues. Acetylation of FoxO proteins by CBP/p300 inhibits their transcriptional activity. Thus, CBP/p300-induced increase in FoxO transcriptional activity appears to be mediated by general histone acetylation. This effect can be overcome by activation of the deacetylase SIRT1 under oxidative-stress conditions (I). P, phosphate; U, ubiquitin. Red arrows indicate negative regulation; green arrows indicate positive regulation. Bars show inhibitory effects.
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