View source for Forkhead box protein O1

{{short description|Protein}}
{{Infobox gene}}
'''Forkhead box protein O1''' ('''FOXO1'''), also known as '''forkhead in rhabdomyosarcoma''' ('''FKHR'''), is a [[protein]] that in humans is encoded by the ''FOXO1'' [[gene]].<ref name="pmid8275086">{{cite journal | vauthors = Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS, Rovera G, Barr FG | title = Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma | journal = Nature Genetics | volume = 5 | issue = 3 | pages = 230–5 | date = November 1993 | pmid = 8275086 | doi = 10.1038/ng1193-230 | s2cid = 12374322 }}</ref> FOXO1 is a [[transcription factor]] that plays important roles in regulation of [[gluconeogenesis]] and [[glycogenolysis]] by [[Insulin#Signal transduction|insulin signaling]], and is also central to the decision for a pre[[adipocyte]] to commit to [[adipogenesis]].<ref name="pmid12530968">{{cite journal | vauthors = Nakae J, Kitamura T, Kitamura Y, Biggs WH, Arden KC, Accili D | title = The forkhead transcription factor Foxo1 regulates adipocyte differentiation | journal = Developmental Cell | volume = 4 | issue = 1 | pages = 119–29 | date = January 2003 | pmid = 12530968 | doi = 10.1016/S1534-5807(02)00401-X | doi-access = free }}</ref> It is primarily regulated through [[phosphorylation]] on multiple residues; its [[transcription (genetics)|transcriptional]] activity is dependent on its phosphorylation state.<ref name="pmid10358075">{{cite journal | vauthors = Rena G, Guo S, Cichy SC, Unterman TG, Cohen P | title = Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B | journal = The Journal of Biological Chemistry | volume = 274 | issue = 24 | pages = 17179–83 | date = June 1999 | pmid = 10358075 | doi = 10.1074/jbc.274.24.17179 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T | title = Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence | journal = The Journal of Biological Chemistry | volume = 274 | issue = 24 | pages = 17184–92 | date = June 1999 | pmid = 10358076 | doi = 10.1074/jbc.274.24.17184 | doi-access = free }}</ref>
== Function ==
=== Adipogenesis ===
[[File:FOXO1 adipogenesis.jpg|thumb|left|FOXO1-dependent inhibition of adipogenesis]]
FOXO1 negatively regulates [[adipogenesis]].<ref name="pmid12535515">{{cite journal | vauthors = Farmer SR | title = The forkhead transcription factor Foxo1: a possible link between obesity and insulin resistance | journal = Molecular Cell | volume = 11 | issue = 1 | pages = 6–8 | date = January 2003 | pmid = 12535515 | doi = 10.1016/S1097-2765(03)00003-0 | doi-access = free }}</ref> 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 [[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.<ref name="pmid16670091">{{cite journal | vauthors = Armoni M, Harel C, Karni S, Chen H, Bar-Yoseph F, Ver MR, Quon MJ, Karnieli E | title = FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity | journal = The Journal of Biological Chemistry | volume = 281 | issue = 29 | pages = 19881–91 | date = July 2006 | pmid = 16670091 | doi = 10.1074/jbc.M600320200 | doi-access = free }}</ref> 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.<ref name="pmid12754525">{{cite journal | vauthors = Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM | title = Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction | journal = Nature | volume = 423 | issue = 6939 | pages = 550–5 | date = May 2003 | pmid = 12754525 | doi = 10.1038/nature01667 | bibcode = 2003Natur.423..550P | doi-access = free }}</ref> 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 [[SOD2]].<ref name="pmid17408630">{{cite journal | vauthors = Adachi M, Osawa Y, Uchinami H, Kitamura T, Accili D, Brenner DA | title = The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells | journal = Gastroenterology | volume = 132 | issue = 4 | pages = 1434–46 | date = April 2007 | pmid = 17408630 | doi = 10.1053/j.gastro.2007.01.033 | url = https://zenodo.org/record/1187188 | doi-access = free }}</ref>
FOXO1 belongs to the [[FOX proteins|forkhead]] family of [[transcription factor]]s that are characterized by a distinct [[fork head domain]]. The specific function of this gene has not yet been determined; however, it may play a role in [[myocyte|myogenic]] growth and differentiation.<ref>{{cite web | title = Entrez Gene: FOXO1 forkhead box O1 (rhabdomyosarcoma)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2308}}</ref> 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.<ref name="pmid21804543">{{cite journal | vauthors = Zhang X, Yalcin S, Lee DF, Yeh TY, Lee SM, Su J, Mungamuri SK, Rimmelé P, Kennedy M, Sellers R, Landthaler M, Tuschl T, Chi NW, Lemischka I, Keller G, Ghaffari S | title = FOXO1 is an essential regulator of pluripotency in human embryonic stem cells | journal = Nature Cell Biology | volume = 13 | issue = 9 | pages = 1092–9 | date = July 2011 | pmid = 21804543 | pmc = 4053529 | doi = 10.1038/ncb2293 }}</ref> In hepatic cells this transcription factor seems to increase the expression of [[phosphoenolpyruvate carboxykinase|PEPCK]] and [[glucose 6-phosphatase|glycogen-6-phosphatase]] (the same enzymes that are blocked via the [[metformin]]/[[AMP-activated protein kinase|AMPK]]/[[small heterodimer partner|SHP]] pathway).  Blocking this transcription factor offers an opportunity for novel therapies for diabetes mellitus.<ref name="pmid20736318">{{cite journal | vauthors = Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka H, Shimaya A, Shimokawa T, Shibasaki M | title = Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice | journal = Molecular Pharmacology | volume = 78 | issue = 5 | pages = 961–70 | date = November 2010 | pmid = 20736318 | doi = 10.1124/mol.110.065714 | s2cid = 212576 }}</ref> In pancreatic alpha-cells FOXO1 is important in regulating prepro-[[glucagon]] expression.<ref name="pmid17062568">{{cite journal | vauthors = McKinnon CM, Ravier MA, Rutter GA | title = FoxO1 is required for the regulation of preproglucagon gene expression by insulin in pancreatic alphaTC1-9 cells | journal = The Journal of Biological Chemistry | volume = 281 | issue = 51 | pages = 39358–69 | date = December 2006 | pmid = 17062568 | doi = 10.1074/jbc.M605022200 | doi-access = free }}</ref> In pancreatic beta cells FOXO1 mediates [[glucagon-like peptide-1]] effects on pancreatic beta-cell mass.<ref name="pmid16644672">{{cite journal | vauthors = Buteau J, Spatz ML, Accili D | title = Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass | journal = Diabetes | volume = 55 | issue = 5 | pages = 1190–6 | date = May 2006 | pmid = 16644672 | doi = 10.2337/db05-0825 | doi-access = free }}</ref>
=== Gluconeogenesis and glycogenolysis ===
[[File:Foxo1 glucose stim.pdf|thumbnail|300 px|left|Depicts insulin-regulated nuclear exclusion of FOXO1 and its effect on transcription of glucose-6 phosphatase]]
When the level of blood glucose is high, the pancreas releases [[insulin]] into the bloodstream. Insulin then causes the activation of [[PI3K]], which subsequently phosphorylates [[Protein kinase B|Akt]]. Akt then phosphorylates FOXO1, causing nuclear exclusion.<ref>{{cite journal | vauthors = Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR, Cohen P | title = Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion | journal = The EMBO Journal | volume = 21 | issue = 9 | pages = 2263–71 | date = May 2002 | pmid = 11980723 | pmc = 125977 | doi = 10.1093/emboj/21.9.2263 }}</ref><ref>{{cite journal | vauthors = Rena G, Prescott AR, Guo S, Cohen P, Unterman TG | title = Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting | journal = The Biochemical Journal | volume = 354 | issue = Pt 3 | pages = 605–12 | date = March 2001 | pmid = 11237865 | pmc = 1221692 | doi = 10.1042/0264-6021:3540605 }}</ref> This phosphorylated FOXO1 is then ubiquitinated and degraded by the proteosome.<ref name="pmid13679577">{{cite journal | vauthors = Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A | title = Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 20 | pages = 11285–90 | date = September 2003 | pmid = 13679577 | pmc = 208749 | doi = 10.1073/pnas.1934283100 | bibcode = 2003PNAS..10011285M | doi-access = free }}</ref> The phosphorylation of FOXO1 is irreversible; this prolongs insulin's inhibitory effect on glucose metabolism and hepatic glucose production. Transcription of [[glucose 6-phosphatase]] subsequently decreases, which consequently decreases the rates of [[gluconeogenesis]] and [[glycogenolysis]].<ref name="pmid17569704">{{cite journal | vauthors = Daitoku H, Fukamizu A | title = FOXO transcription factors in the regulatory networks of longevity | journal = Journal of Biochemistry | volume = 141 | issue = 6 | pages = 769–74 | date = June 2007 | pmid = 17569704 | doi = 10.1093/jb/mvm104 }}</ref> FOXO1 also activates transcription of [[phosphoenolpyruvate carboxykinase]], which is required for gluconeogenesis.<ref name="pmid11696581"/>  The activity of FOXO1 is also regulated through [[CREB-binding protein|CBP]] induced acetylation<ref name="pmid16076959">{{cite journal | vauthors = Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A | title = Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 32 | pages = 11278–83 | date = August 2005 | pmid = 16076959 | pmc = 1183558 | doi = 10.1073/pnas.0502738102 | bibcode = 2005PNAS..10211278M | doi-access = free }}</ref> on [[Lysine|Lys]]-242, Lys-245, and Lys-262. These lysine residues are located within the [[DNA-binding domain]]; [[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 [[Akt]]. Mutating Ser-253 to Ala-253 makes FOXO1 constitutively active. [[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.<ref name="pmid17681146">{{cite journal | vauthors = Jing E, Gesta S, Kahn CR | title = SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation | journal = Cell Metabolism | volume = 6 | issue = 2 | pages = 105–14 | date = August 2007 | pmid = 17681146 | pmc = 2083635 | doi = 10.1016/j.cmet.2007.07.003 }}</ref>
=== Apoptosis ===
FOXO1 may play an important role in [[apoptosis]] because it is phosphorylated and inhibited by [[Protein kinase B|AKT]].<ref name="Lu_2011">{{cite journal | vauthors = Lu H, Huang H | title = FOXO1: a potential target for human diseases | journal = Current Drug Targets | volume = 12 | issue = 9 | pages = 1235–44 | date = August 2011 | pmid = 21443466 | pmc = 4591039 | doi=10.2174/138945011796150280}}</ref> When FOXO1 is over expressed in human [[LNCaP]] prostate [[cancer cells]], it causes [[apoptosis]].<ref name="Lu_2011" /> Also, FOXO1 regulates TNF-related apoptosis-inducing ligand ([[TRAIL]]), which caused FOXO1-induced [[apoptosis]] in the human [[prostate cancer]] cell line [[LAPC4]] when FOXO1 adenovirus-mediated overexpression was used.<ref name="Lu_2011" /> FOXO1 upregulates Fas ligand ([[Fas ligand|FasL]]) transcriptionally resulting in [[apoptotic cell death]].<ref name="Lu_2011" /> Additionally, FOXO1 trans-activate [[BCL2L11|Bim]] protein, which a member of the [[Bcl-2 family]] that promotes [[apoptosis]] and plays a role in the intrinsic mitochondrial apoptotic pathway.<ref name="Lu_2011" /> Further, it was revealed that [[DNA]] damage-induced cell death in [[TP53|p53]]-deficient and [[TP53|p53]]-proficient cells was reduced when human FOXO1 is silenced by [[Small interfering RNA|siRNA]].<ref name="Lu_2011" /> In [[type 2 diabetes]] the [[beta cell]]s of the pancreas, which normally produce [[insulin]] undergo apoptosis, which greatly reduces insulin production. [[Fatty acid]]s in the beta cells activate FOXO1, resulting in apoptosis of the beta cells.<ref name="pmid31831356">{{cite journal | vauthors=Sun T, Han X | title=Death versus dedifferentiation: The molecular bases of beta cell mass reduction in type 2 diabetes | journal=[[Seminars in Cell and Developmental Biology]] | year=2019 | volume=103 | pages=76–82 | doi = 10.1016/j.semcdb.2019.12.002 | pmid=31831356| s2cid=209341381 }}</ref>
=== Cell Cycle Regulation ===
FOXO1 activation plays a role in [[cell cycle progression]] regulation.<ref name="Lu_2011" /> The transcription and half- life of [[Cyclin-dependent kinase inhibitor protein|cyclin-dependent kinase inhibitor]] p27KIP1 rises when FOXO1 is active.<ref name="Lu_2011" /> A study detects that FOXO1 regulates the nuclear localization of p27KIP1 in porcine granulosa cells and impacts [[cell cycle]] progression.<ref name="Lu_2011" /> Furthermore, FOXO1-mediated cell cycle arrest is linked with [[cyclin D1]] and [[cyclin D2]] suppression in mammals.<ref name="Lu_2011" /> It was detected that human FOXO1 is linked with the [[cyclin D1]] promoter using chromatin immunoprecipitation assays ([[ChIP assay]]s).<ref name="Lu_2011" /> H215R is a human FOXO1 mutant, which cannot bind to the canonical FRE to induce expression of p27KIP1, repress [[cyclin D1]] and [[cyclin D2]] promoter activity and encourages [[cell cycle]] arrest at cyclin G1 ([[CCNG1]]).<ref name="Lu_2011" /> As a result of that, activation of FOXO1 prevents the [[cell-division cycle]] at cyclin G1 ([[CCNG1]]) out of one of two ways stimulating or suppressing gene transcription.<ref name="Lu_2011" />
== 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 (genetics)|promoter]] for [[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.<ref name="pmid11696581">{{cite journal | vauthors = Nakae J, Kitamura T, Silver DL, Accili D | title = The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression | journal = The Journal of Clinical Investigation | volume = 108 | issue = 9 | pages = 1359–67 | date = November 2001 | pmid = 11696581 | pmc = 209440 | doi = 10.1172/JCI12876 }}</ref> However, when FOXO1 is phosphorylated by [[AKT|Akt]] on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then [[Ubiquitin#Ubiquitylation|ubiquitinated]] and degraded. The [[phosphorylation]] of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.
== Regulation ==
There are three processes, namely [[acetylation]], [[phosphorylation]], and [[ubiquitin]]ation that are responsible for regulation of the activity of forkhead box O1 (FOXO1).<ref name="Wang_2014">{{cite journal | vauthors = Wang Y, Zhou Y, Graves DT | title = FOXO transcription factors: their clinical significance and regulation | journal = BioMed Research International | volume = 2014 | pages = 925350 | date = April 2014 | pmid = 24864265 | pmc = 4016844 | doi = 10.1155/2014/925350 | doi-access = free }}</ref>
=== Phosphorylation ===
[[Phosphorylation]] of the FOXO1 protein is a result of the activation of the [[PI3K/AKT/mTOR pathway|PI3K /AKT pathway]].<ref name="Wang_2014"/> Serum and glucocorticoid-inducible kinase [[SGK1|SGK]] can also phosphorylate and inactivate FOXO1 transcription factor.<ref name="Lu_2011" /> FOXO1 translocate from the [[Cell nucleus|nucleus]] to [[cytoplasm]] and inactivate through [[phosphorylation]] at well-defined sites by AKT/SGK1 protein kinases.<ref name="Wang_2014" /> FOXO1 transcription factor can phosphorylate directly by [[Protein kinase B|AKT]]/[[SGK1]] on three sites T24, S256 and S319.<ref>{{cite journal | vauthors = Hedrick SM, Hess Michelini R, Doedens AL, Goldrath AW, Stone EL | title = FOXO transcription factors throughout T cell biology | journal = Nature Reviews. Immunology | volume = 12 | issue = 9 | pages = 649–61 | date = September 2012 | pmid = 22918467 | pmc = 3875397 | doi = 10.1038/nri3278 }}</ref>  Additionally, FOXO1 loses its interactions with [[DNA]] when phosphorylated by [[Protein kinase B|AKT]]/[[SGK1]] because S256, which is one of the three AKT/SGK sites, changes the [[DNA-binding domain]] charge from a positive charge to a negative charge.<ref name="Wang_2014" />
Insulin signaling substrates 1 and 2 of the insulin-signaling cascade also regulate FOXO1 through phosphorylation by [[Protein kinase B|AKT]].<ref name="Wang_2014" /> [[Protein kinase B|AKT]], which is referred to as protein kinase B, phosphorylates FOXO1 and accumulates in the [[cytosol]].<ref name="Wang_2014" />
[[Casein kinase 1]], a growth factor-activated protein kinase, also phosphorylates and potentiates FOXO1 and translocates FOXO1 to the [[cytoplasm]].<ref name="Wang_2014" />
== Research ==
Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of [[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.<ref name="pmid12219087">{{cite journal | vauthors = Nakae J, Biggs WH, Kitamura T, Cavenee WK, Wright CV, Arden KC, Accili D | title = Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 | journal = Nature Genetics | volume = 32 | issue = 2 | pages = 245–53 | date = October 2002 | pmid = 12219087 | doi = 10.1038/ng890 | s2cid = 12234973 }}</ref>  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 [[rosiglitazone]], which is a commonly prescribed anti-diabetic drug.<ref name="pmid19289458">{{cite journal | vauthors = Kim JJ, Li P, Huntley J, Chang JP, Arden KC, Olefsky JM | title = FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue | journal = Diabetes | volume = 58 | issue = 6 | pages = 1275–82 | date = June 2009 | pmid = 19289458 | pmc = 2682681 | doi = 10.2337/db08-1001 }}</ref> These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes.
In diabetes (both type 1 and type 2), gluconeogenesis in the kidney contributes more to blood glucose than it does in normal subjects.<ref name="pmid30370538">{{cite journal | vauthors=Swe MT, Pongchaidecha A, Chatsudthipong V, Chattipakorn N, Lungkaphin A | title=Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions | journal=[[Journal of Cellular Physiology]] | volume=234 | issue=6 | pages=8134–8151 | year=2019 |  doi = 10.1002/jcp.27598 |  pmid=30370538| s2cid=53097552 }}</ref> Enhancing suppression of FOXO1 by insulin can reduce gluconeogenesis in both the liver and kidney.<ref name="pmid30370538" />
In HFD-fed mice, the combination of FOXO1 and Notch-1 haploinsufficiency was more effective at restoring insulin sensitivity than FOXO1 haploinsufficiency alone.<ref name="pmid21804540">{{cite journal | vauthors = Pajvani UB, Shawber CJ, Samuel VT, Birkenfeld AL, Shulman GI, Kitajewski J, Accili D | title = Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner | journal = Nature Medicine | volume = 17 | issue = 8 | pages = 961–7 | date = July 2011 | pmid = 21804540 | pmc = 3387563 | doi = 10.1038/nm.2378 }}</ref>
Insulin-producing cells could be generated through the inhibition of FOXO1 in intestinal [[organoid]]s generated from intestinal stem cells isolated from adult tissue.<ref name="pmid24979718">{{cite journal | vauthors = Bouchi R, Foo KS, Hua H, Tsuchiya K, Ohmura Y, Sandoval PR, Ratner LE, Egli D, Leibel RL, Accili D | title = FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures | journal = Nature Communications | volume = 5 | pages = 4242 | date = June 2014 | pmid = 24979718 | pmc = 4083475 | doi = 10.1038/ncomms5242 | bibcode = 2014NatCo...5.4242B }}</ref>
== Clinical significance ==
* Translocation of this gene with [[PAX3]] has been associated with [[alveolar rhabdomyosarcoma]].<ref name="pmid8275086"/><ref name="pmid18457914">{{cite journal | vauthors = Linardic CM | title = PAX3-FOXO1 fusion gene in rhabdomyosarcoma | journal = Cancer Letters | volume = 270 | issue = 1 | pages = 10–8 | date = October 2008 | pmid = 18457914 | pmc = 2575376 | doi = 10.1016/j.canlet.2008.03.035 }}</ref>
* In [[Gluconeogenesis]], FOXO1 gene regulates the [[glucose]] levels due to the low output of hepatic [[glucose]].<ref name="Wang_2014" />  In mice, it cuts fasting blood [[glucose]] levels by inhibiting formulation of the [[Glucogenic amino acid|gluconeogenic]] genes.<ref name="Wang_2014" />
* FOXO1 plays a role in the protection of cells from [[oxidative stress]].<ref name="Wang_2014" /> It seems to promote cell death when [[oxidative stress]] is high in tissues that are involved in diabetic complications.<ref name="Wang_2014" /> In such situations, it has a destructive role instead of a protective role.<ref name="Wang_2014" />
* FOXO1 helps in [[wound healing]] in mice through coordination of response of [[keratinocyte]]s and functions in [[keratinocyte]]s to bring down [[oxidative stress]].<ref name="Wang_2014" /> [[Wound healing]] is a very complicated biological process and studies have indicated that FOXO1 transcription factor helps in orchestrating events that enhance the healing process in [[keratinocyte]]s.<ref name="Xiao_2015">{{cite journal | vauthors = Xiao E, Graves DT | title = Impact of Diabetes on the Protective Role of FOXO1 in Wound Healing | journal = Journal of Dental Research | volume = 94 | issue = 8 | pages = 1025–6 | date = August 2015 | pmid = 25978971 | pmc = 530387 | doi = 10.1177/0022034515586353 }}</ref> Localization of FOXO1 nuclear increased four times in [[Wound healing|wound-healing]] [[keratinocyte]]s.<ref name="Xiao_2015" /> It encourages the migration of the [[keratinocyte]]s through upregulating the growth factor.<ref name="Xiao_2015" />
* In the [[Innate immune system|Innate Immune system]], FOXO1 has been proved to enhance [[inflammation]] through increasing formulation of several proinflammatory genes.<ref name="Wang_2014" />  It mediates formulation of [[proinflammatory cytokine]]s in response to high [[glucose]] levels, [[TNF]] and LPS stimulation.<ref name="Wang_2014" />
* In [[Adaptive immune system|Adaptive Immunity system]], FOXO1 regulates the return of peripheral [[B cell]]s by upregulation of L-section and controls class-switch recombination of peripheral [[B cell]]s and in [[T cell]]s it enhances survival of [[CD8]] memory.<ref name="Wang_2014" />
* In [[Carcinogenesis]], FOXO1 plays a role of a tumor suppressor and its inactivation has been documented in many kinds of human [[cancer]].<ref name="Wang_2014" />  It suppresses survival of [[Neoplasm|tumor cells]] by inducing [[apoptosis]] in prostate cancer cells and glioma cells by upregulating the proapoptotic factors.<ref name="Wang_2014" />  Increased activation of FOXO1 may inhibit the [[metastasis]] of the prostate cancer cells to other organs by suppressing the migration and invasion or suppressing the [[Runt domain|Runt-domain]] containing [[RUNX2|Runx2]] transcriptional activity.<ref name="Wang_2014" />
== Interactions ==
FOXO1 has been shown to [[Protein-protein interaction|interact]] with:
* [[androgen receptor]],<ref name="pmid12482965">{{cite journal | vauthors = Li P, Lee H, Guo S, Unterman TG, Jenster G, Bai W | title = AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR | journal = Molecular and Cellular Biology | volume = 23 | issue = 1 | pages = 104–18 | date = January 2003 | pmid = 12482965 | pmc = 140652 | doi = 10.1128/MCB.23.1.104-118.2003 }}</ref>
* [[estrogen receptor alpha]],<ref name="pmid11435445">{{cite journal | vauthors = Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ | title = Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family | journal = The Journal of Biological Chemistry | volume = 276 | issue = 36 | pages = 33554–60 | date = September 2001 | pmid = 11435445 | doi = 10.1074/jbc.M105555200 | doi-access = free }}</ref>
* [[CREB-binding protein]],<ref name="pmid10973497">{{cite journal | vauthors = Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC | title = DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 19 | pages = 10412–7 | date = September 2000 | pmid = 10973497 | pmc = 27038 | doi = 10.1073/pnas.190326997 | bibcode = 2000PNAS...9710412N | doi-access = free }}</ref> and
* [[TSC2|tuberous sclerosis protein 2]].<ref name="pmid17077083">{{cite journal | vauthors = Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J | title = Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway | journal = The Journal of Biological Chemistry | volume = 281 | issue = 52 | pages = 40242–51 | date = December 2006 | pmid = 17077083 | doi = 10.1074/jbc.M608116200 | doi-access = free }}</ref>
== References ==
{{reflist | colwidth = 35em}}
== External links ==
* {{MeshName|FOXO1A+protein,+human}}
{{NLM content}}
{{Transcription factors|g3}}
{{Use dmy dates|date=April 2017}}
[[Category:Forkhead transcription factors]]