The Fox (forkhead box) family is a group of transcription factors with a wing-like helix structure in the DNA binding region. FoxO is a subfamily of the Fox (forkhead box) family. In humans, there are four FoxO isoforms: FoxO1, FoxO2, FoxO3a, FoxO4.
In the FoxO signaling pathway, active FoxO regulates the expression of downstream genes, mediating many cellular physiological processes.
FoxO has three highly conservative PKB phosphorylation sites, including Thr24, Ser256, and Ser319. In the absence of stimulators, FoxO remains in the nucleus and exists in dephosphorylated form. Nuclear FoxO regulates the expression of related target genes, which affects many cellular physiological processes such as cell cycle, apoptosis, metabolism and oxidative stress, immune regulation, etc.
When stimulated by growth factors or insulin, FoxO is phosphorylated and becomes inactive. Phosphorylated FoxO changes its conformation and then binds to the 14-3-3 protein, mediating the export of FoxO from the nucleus to the cytoplasm and reducing the expression of the target genes of FOXO. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy-sensing AMP-activated protein kinase (AMPK) dephosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple molecules through several post-translational modifications such as phosphorylation, acetylation, methylation, and ubiquitylation.
Many studies have demonstrated that FoxO3a can bind to the promoter of Bim. Bim is a pro-apoptotic protein, initiating apoptosis mediated by mitochondria.
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