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First published online July 23, 2007
doi: 10.1242/10.1242/jcs.001222

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Dynamic FoxO transcription factors

¹ Cancer Center and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
² Departments of Urology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

View larger version (28K): [in this window] [in a new window]   Fig. 1. Domain structure of the FoxO1 protein (A) and the major post-translational modifications or protein interactions within and near the forkhead (FKH) domain and the nuclear localization signal (NLS) (B). NES, nuclear export signal; TA, the transactivation domain. The secondary structures predicted from the FKH domain of HNF-3 – four -helices (H1, H2, H3 and H4) and two winged-loops (W1 and W2) – are included. Residues representing the identified or potential post-translational modifications, and the site for interaction with Skp2, that inhibit FoxO1 are indicated in red; those that promote FoxO1 activity are in green. Preferred Akt- and SGK-phosphorylation sites are underlined.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Transcriptional activity and regulation of FoxO transcription factors during the cell cycle. Negative regulators of the G1/S transition of the cell cycle, such as p27KIP1, p21WAF1 and p130, are upregulated by the FoxO transcription factors. Moreover, expression of positive regulators, such as cyclin D1 and D2, is repressed by FoxO proteins. Activation of FoxO proteins also induces the expression of Gadd45 and cyclin G2, resulting in cell cycle arrest at G2/M. By contrast, activation of the transcriptional activity of FoxO proteins induces expression of cyclin B and polo-like kinase (Plk), two key genes during mitosis. These FoxO-dependent transcriptional programs appear to be tightly controlled by various signaling pathways during the cell cycle. Upon stimulation with growth factors, quiescent (G0) cells re-enter G1 phase, and Akt is activated. Activation of Akt can lead to the phosphorylation and inhibition of FoxO proteins. Moreover, activated Akt also induces the expression of Skp2, with which it works in concert to promote the degradation of FoxO proteins, at least in the case of FoxO1. With the progression of cells into S phase, CDK2 is highly activated owing to E2F-dependent expression of cyclin E and Cdc25A, two activators of CDK2. Activated CDK2 can phosphorylate and inhibit FoxO proteins, such as FoxO1 and FoxO6. At the end of DNA synthesis, E2F and cyclin E can be degraded through a Skp2-dependent mechanism and, therefore, CDK2-mediated inhibition of FOXO1 is diminished. It is possible that the inhibitory function of FoxO proteins at G2/M is under the control of Skp2 only until anaphase, when Skp2 is targeted for degradation by the anaphase-promoting complex/cyclosome (APC/C) E3 ligase.

View larger version (79K): [in this window] [in a new window]   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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