Background：Forkhead box O-class (FOXO) transcription factors are mammalian homologue of DAF-16, a known lifespan regulator of Caenorhabditis elegans. FOXO transcription factors, such as FOXO1, FOXO3a, and FOXO4, have been linked to the regulation of cell cycle, apoptosis, DNA repair, oxidative stress, and metabolism. FOXO proteins are proposed to be dual regulated by Akt-mediated phosphorylation and Skp2-mediated ubiquitination, which are usually initiated by growth factors and cytokines. FOXO proteins are also activated by stress, which induces gene expression that contributes to cell cycle arrest, implicating FOXO proteins as tumor suppressors. Specifically, FOXO3a (FKHR-L1) is a transcriptional activator for apoptosis in the absence of survival factors, such as in neural cell death triggered by oxidative stress. In the presence of survival factors like IGF-1, AKT1/PKB phosphorylates on Thr-32 and Ser-253. FOXO3a is inactivated when phosphorylated by AKT1 on Thr-32 and Ser-253.
