[1, 4-6, 10-12] FOXO transcriptional activity is regulated by a complex array of posttranslational modifications (PTMs). In many circumstances, the primary regulatory event is protein kinase

B (Akt)-mediated phosphorylation of three conserved amino acids, two serines, and one threonine, that Fulvestrant ic50 results in binding to 14-3-3 and nuclear export of the protein. A conceptual theme that has emerged from the study of multiple FOXOs is that they are a major part of the mechanism that allows cells to transition between a fed/unstressed state where cell proliferation is favored and a fasting/stressed state which initially favors cell cycle arrest, DNA repair, and antioxidant enzyme induction, but can proceed toward apoptosis and cell death HSP inhibitor (see Fig. 1). The action of the FOXO factors varies depending of the nature of the cell type and circumstances. A combination of different FOXO proteins, each with specific PTM combinations, is able to tailor the response to the situation. FOXO1 plays a major role in regulating the insulin

response, and the liver is one of its critical sites of action. The liver adapts to feeding through several insulin mediated events including increasing glucose uptake into hepatocytes, suppressing gluconeogenesis and glycogenolysis, and upregulating glycogen synthesis. In fasting, the withdrawal of insulin stimulation results in gluconeogensis through an upregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase), and induction of autophagy. This response is largely dependent on the interplay between Akt and FOXO1. The role of FOXO1 in the adaptation to fasting has been largely documented by animal studies of overexpression and heterozygous null expression leading to increased or decreased FOXO1 expression. When FOXO1 is

constitutively expressed in the liver, fasting blood glucose rises.[13] Conversely, liver specific FOXO1 knock-out mice develop fasting hypoglycemia.[14] The mechanism behind these phenomena appears to be relatively straightforward. FOXO1 is active in the fasted state where it is dephosphorylated medchemexpress at the Akt sites and localized in the nucleus. This results in the transcriptional induction of two gluconeogenic enzymes, glucose-6-phosphatase catalytic subunit (G6Pc), and PEPCK[15] and increased hepatic glucose production. In the fed state, insulin signaling activates phosphatidylinositol 3-kinase (PI3)-kinase and the subsequent production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) activates Akt. Akt phosphorylates FoxO1 at Thr24, Ser253, and Ser316 leading to its nuclear exportation and inactivation[16] with subsequent suppression of gluconeogenesis. The importance of FOXO1 as a counter of Akt in the glycogen synthesis-gluconeogensis balance has been recently demonstrated using liver specific knock-out mice for both Akt and FOXO1.