FoxO3a and disease progression

Figure 1 Forkhead box O3a target genes. Forkhead box O (FoxO)3a transcriptionally activates several target genes. FoxO3a binds to the promoter of apoptosis inducing genes, such as Bim, FasL and TRAIL, and to the promoter of cell cycle inhibitors, such as p27 and p21. FoxO3a also activates autophagy genes Gabarapl1, ATG12, etc. A recent study showed that FoxO3a also participates in the activation of stress response genes, such as MnSOD and catalase in response to oxidative stress.

Figure 2 Major phosphorylation and acetylation residues of FoxO3a. Post-translational modification sites of FoxO3a. Shown are sites of serine/threonine phosphorylation by Akt/SGK, MST1, IKKβ or the residues acetylated by CBP or unidentified acetyl transferases (?) on FoxO3a domains[12]. FKH: Forkhead DNA binding domain; NLS: Nuclear localization signal; NES: Nuclear export sequence; TA: Transactivation domain; Akt: Protein kinase B; MST1: Mammalian sterile 20 like kinase-1; CBP: The cyclic–AMP responsive element binding (CREB) binding protein, IKKβ: Ikβ kinase; SGK: Serum-and glucocorticoid-induced protein kinase.

Figure 3 Forkhead box O3a localization by phosphorylation and dephosphorylation. Forkhead box O (FoxO)3a becomes translocated to the cytoplasm when phosphorylated on ser 253 residue by Akt or SGK. FoxO3a is then bound to 14-3-3 and this interaction promotes its degradation by the proteasome. In contrast, FoxO3a is dephosphorylated by protein phosphatase-2A and this opposite event facilitates its re-location into the nucleus, thereby activating its target genes. SGK: Serum-and glucocorticoid-induced protein kinase; Akt: Protein kinase B.