(A) Upon stimulation with growth factors or insulin, Akt directly phosphorylates FoxO factors at three conserved residues, promoting their export from the nucleus by binding with the chaperone 14-3-3, and thus resulting in the inhibition of FoxO-dependent transcription. In the presence of growth factors or insulin FoxO-dependent transcription is inhibited promoting cellular proliferation and survival, but also rendering the cell sensitive to oxidative damage. (B) Oxidative stress induces the phosphorylation, acetylation and monoubiquitination of FoxO factors at a number of regulatory sites by factors such as AMPK (AMP-dependent kinase), JNK (Jun-N-terminal kinase), MST1 (mammalian Ste20-like kinase) and CBP (CREB binding protein). In response to oxidative stress, FoxO factors translocate to the nucleus and bind to the deacetylase Sirt1. Key modification signatures appear to recruit FoxO factors to specific genes involved in cell-cycle arrest and the response to stress. p27, cyclin-dependent kinase inhibitor; MnSOD, manganese superoxide dismutase; Bim, pro-apoptotic Bcl2-interacting mediator of cell death; Gadd45α, growth arrest- and DNA damage-inducible gene 45 α.

FoxO-dependent transcription serves to increase systemic glucose levels by regulating gluconeogenesis, insulin secretion, and food intake in the regulatory cells of the organism such as the hepatocytes, pancreatic β-cells, and hypothalamic neurons. In energy-utilizing cells, such as myocytes and neurons, the FoxO factors appear to be activated in response to harsh environment conditions such as starvation and oxidative stress to initiate atrophy, autophagy or apoptosis. In T cells, FoxO factors attenuate proliferation and hyperactivation. In the endothelial cells of the vascular system, the FoxO factors regulate genes to suppress proliferation and inhibit migration. FoxO factors also display a crucial role in the maintenance of hematopoietic stem cells (HSC) by coordinating quiescence, stress resistance and terminal differentiation. Overall, FoxO factors appear to promote an organismal metabolic shutdown in response to harsh environmental conditions, such as starvation, to enable the organism to survive in anticipation of improved environmental conditions.