FOXO1

Forkhead box protein O1 (FOXO1) also known as forkhead in rhabdomyosarcoma is a is_associated_with::protein that in humans is encoded by the FOXO1 is_associated_with::gene. FOXO1 is a is_associated_with::transcription factor that plays important roles in regulation of is_associated_with::gluconeogenesis and is_associated_with::glycogenolysis by insulin signaling, and is also central to the decision for a preis_associated_with::adipocyte to commit to is_associated_with::adipogenesis. It is primarily regulated through is_associated_with::phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

Mechanism of action
In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for is_associated_with::glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production. However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The is_associated_with::phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.

Adipogenesis
Recent research has demonstrated that FOXO1 also negatively regulates is_associated_with::adipogenesis. Presently, the exact mechanism by which this is accomplished is not entirely understood. In the currently accepted model, FOXO1 negatively regulates adipogenesis by binding to the promoter sites of is_associated_with::PPARG and preventing its transcription. Rising levels of PPARG are required to initiate adipogenesis; by preventing its transcription, FOXO1 is preventing the onset of adipogenesis. During stimulation by insulin, FOXO1 is excluded from the nucleus and is subsequently unable to prevent transcription of PPARG and inhibit adipogenesis. However, there is substantial evidence to suggest that there are other factors that mediate the interaction between FOXO1 and the PPARG promoter, and that inhibition of adipogenesis is not entirely dependent on FOXO1 preventing transcription of PPARG. Other research demonstrates that the failure to commit to adipogenesis is primarily due to active FOXO1 arresting the cell in G0/G1 through activation of yet unknown downstream targets, with a putative target being is_associated_with::SOD2.

FOXO1 belongs to the forkhead family of is_associated_with::transcription factors that are characterized by a distinct is_associated_with::fork head domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. FOXO1 is essential for the maintenance of human ESC pluripotency. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. In hepatic cells this transcription factor seems to increase the expression of PEPCK and glycogen-6-phosphatase (the same enzymes that are blocked via the is_associated_with::metformin/AMPK/SHP pathway). Blocking this transcription factor offers an opportunity for novel therapies for diabetes mellitus. In pancreatic alpha-cells FOXO1 is important in regulating prepro-is_associated_with::glucagon expression. In pancreatic beta cells FOXO1 mediates is_associated_with::glucagon-like peptide-1 effects on pancreatic beta-cell mass.

Gluconeogenesis and glycogenolysis
When the level of blood glucose is high, the pancreas releases is_associated_with::insulin into the bloodstream. Insulin then causes the activation of is_associated_with::PI3K, which subsequently phosphorylates Akt. Akt then phosphorylates FOXO1, causing nuclear exclusion. This phosphorylated FOXO1 is then ubiquitinated and degraded by the proteosome. The phosphorylation of FOXO1 is irreversible; this prolongs insulin's inhibitory effect on glucose metabolism and hepatic glucose production. Transcription of is_associated_with::glucose 6-phosphatase subsequently decreases, which consequently decreases the rates of gluconeogenesis and glycogenolysis. Certain research groups have also recently suggested that FOXO1 also activates transcription of is_associated_with::phosphoenolpyruvate carboxykinase, which is required for gluconeogenesis. Recent research has demonstrated that the activity of FOXO1 is also regulated through CBP induced acetylation on Lys-242, Lys-245, and Lys-262. These lysine residues are located within the is_associated_with::DNA-binding domain; is_associated_with::acetylation inhibits the ability of FOXO1 to interact with the glucose-6 phosphatase promoter by decreasing the stability of the FOXO1-DNA complex. Additionally, this acetylation increases the rate of phosphorylation on Ser-253 by is_associated_with::Akt. Interestingly, mutating Ser-253 to Ala-253 makes FOXO1 constitutionally active. Further research has demonstrated that is_associated_with::SIRT1 reverses this acetylation process; however, the exact mechanism by which SIRT1 deacetylates FOXO1 is still under investigation; presently, acetylation is thought to mitigate the transcriptional activity of FOXO1 and thereby provide an additional level of metabolic regulation that is independent of the insulin/PI3K pathway.

Clinical significance
Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of is_associated_with::type 2 diabetes. In the insulin-resistant murine model, there is increased hepatic glucose production due to a loss in insulin sensitivity; the rates of hepatic gluconeogenesis and glycogenolysis are increased when compared to normal mice; this is presumably due to un-regulated FOXO1. When the same experiment was repeated with haploinsufficient FOXO1, insulin sensitivity was partially restored, and hepatic glucose production subsequently decreased. Similarly, in mice fed with a high fat diet (HFD), there is increased insulin resistance in skeletal and liver cells. However, when haploinsufficient FOXO1 mice were treated with the same HFD, there was a notable decrease in insulin resistance in both skeletal and liver cells. This effect was significantly augmented by the simultaneous administration of is_associated_with::rosiglitazone, which is a commonly prescribed anti-diabetic drug. These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes. Current research is investigating the potential of combining FOXO1 and is_associated_with::Notch-1 haploinsufficiency in mice; preliminary results suggest that in HFD-fed mice, the combination of FOXO1 and Notch-1 haploinsufficiency was more effective at restoring insulin sensitivity than FOXO1 haploinsufficiency alone. Translocation of this gene with is_associated_with::PAX3 has been associated with is_associated_with::alveolar rhabdomyosarcoma.

Interactions
FOXO1 has been shown to interact with:
 * is_associated_with::androgen receptor,
 * is_associated_with::estrogen receptor alpha,
 * is_associated_with::CREB-binding protein, and
 * tuberous sclerosis protein 2.