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HGNC Approved Gene Symbol:FOXO1
Cytogenetic location:13q14.11 Genomic coordinates(GRCh38) :13:40,555,667-40,666,641 (from NCBI)
By searching for genes in a region of chromosome 13 involved in a translocation causing alveolar rhabdomyosarcoma (268220), followed by sequencing overlapping cDNA clones from several libraries,Galili et al. (1993) obtained full-length FOXO1A, which they called FKHR. The deduced 655-amino acid protein has an alanine-rich region, a proline-rich region with characteristics of an SH3-binding site, and a DNA-binding forkhead domain of about 100 amino acids in its N-terminal half. Northern blot analysis detected a 6.5-kb transcript in all normal adult tissues examined, as well as in lymphoblasts and fibroblasts. Immunoprecipitated FOXO1A had an apparent molecular mass of 56 kD by SDS-PAGE.
Using RT-PCR and immunohistochemical analysis of mouse embryos at embryonic day 15.5,Teixeira et al. (2010) detected Foxo1 mRNA and protein expression in brain, tongue, liver, and cartilage. Highest expression was in areas of intramembranous bone formation, such as calvaria, and endochondral bone formation, such as diaphysis of long bones.
Galili et al. (1993) determined that the 5-prime upstream region of the FOXO1A gene includes a CpG island.
Galili et al. (1993) determined that the FOXO1A gene maps to chromosome 13q14.
Anderson et al. (1998) identified a processed pseudogene that is similar to FOXO1A and maps to chromosome 5q35.2-q35.3.
Role in Cell Cycle Regulation and Apoptosis
Medema et al. (2000) demonstrated that overexpression of the forkhead transcription factors FKHR, AFX (MLLT7;300033), or FKHRL1 (FOXO3A;602681) caused growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumor suppressor PTEN (601728).Medema et al. (2000) demonstrated that AFX transcriptionally activates p27(KIP1), resulting in increased protein levels, and concluded that AFX-like proteins are involved in cell cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.
By analyzing PTEN-deficient tumor cell lines,Nakamura et al. (2000) determined that PTEN deficiency leads to aberrant localization of FKHR to the cytoplasm. Restoration of PTEN expression restored FKHR to the nucleus and restored transcriptional activation.Nakamura et al. (2000) also found evidence that FKHR is an effector of PTEN activation, in that FKHR induced apoptosis in cells that undergo PTEN-mediated apoptosis, and FKHR mediated G1 arrest in cells that undergo PTEN-mediated cell cycle arrest.
Modur et al. (2002) found that both FKHR and FKHRL1 were highly expressed in normal prostate. They also noted that, in PTEN-deficient prostate carcinoma cell lines, FKHR and FKHRL1 were cytoplasmically sequestered and inactive, and expression of TRAIL (603598), a proapoptotic effector, was decreased.Modur et al. (2002) determined that TRAIL is a direct target of FKHRL1, and they hypothesized that the loss of PTEN contributes to increased tumor cell survival through decreased transcriptional activity of FKHR and FKHRL1 followed by decreased TRAIL expression and apoptosis.
Huang et al. (2006) found that CDK2 (116953) specifically phosphorylated FOXO1 at ser249 in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of FOXO1. This phosphorylation was abrogated upon DNA damage through the cell cycle checkpoint pathway that is dependent on the protein kinases CHK1 (603078) and CHK2 (604373). Moreover, silencing of FOXO1 by small interfering RNA diminished DNA damage-induced death in both p53 (191170)-deficient and p53-proficient cells. This effect was reversed by restored expression of FOXO1 in a manner depending on phosphorylation of ser249.Huang et al. (2006) concluded that functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage.
Yuan et al. (2008) found that CDK1 (116940) phosphorylated the transcription factor FOXO1 at serine-249 in vitro and in vivo. The phosphorylation of FOXO1 at serine-249 disrupted FOXO1 binding with 14-3-3 (see601289) proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, CDK1 induced FOXO1 serine-249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk;602098).Yuan et al. (2008) concluded that their findings defined a conserved signaling link between CDK1 and FOXO1 that may have a key role in diverse biologic processes including the degeneration of postmitotic neurons.
By Northern blot analysis,Berry et al. (2008) found that FOXC1 (601090) induced the expression of the apoptosis regulator FOXO1A about 13-fold. The promoter regions of zebrafish and human FOXO1A contain consensus FOXC1 binding sites; chromatin immunoprecipitation and reporter gene assays confirmed that FOXC1 bound these sites and activated the FOXO1A promoter. Knockdown of FOXC1 in human trabecular meshwork cells reduced FOXO1A expression and increased cell death in response to oxidative stress. Morpholino-mediated knockdown of Foxo1a in zebrafish embryos resulted in increased cell death in the developing eye.
Using bioinformatics analysis,McLoughlin et al. (2014) identified a conserved putative MIR183 (611608) target site in the 3-prime UTR of FOXO1 mRNA. They also identified a human-specific MIR183 target site in the 3-prime UTR of human FOXO1 that was created by a single nucleotide change relative to mouse and chimpanzee Foxo1. Reporter gene assays and site-directed mutagenesis studies revealed that synthetic MIR183 downregulated expression of FOXO1 in a dose-dependent manner from the human-specific MIR183 target site, but not the conserved MIR183 target site. Overexpression of pre-MIR183 downregulated FOXO1 expression and increased invasive potential in human ONS-76 medulloblastoma cells, but not in mouse C17-2 cerebellar stem cells. Overexpression of pre-MIR183 decreased cell proliferation in both ONS-76 and C17-2 cells, whereas protection of the MIR183 target site in the 3-prime UTR of FOXO1 rescued proliferation in ONS-76 cells, but not in C17-2 cells, suggesting that MIR183 targets other than Foxo1 contribute to proliferation in mouse cells.
Role in Insulin Signaling and Energy Metabolism
Using wildtype and mutant alleles of FOXO1,Puigserver et al. (2003) demonstrated that PPARGC1 (604517) binds and coactivates FOXO1 in a manner inhibited by AKT-mediated phosphorylation. Furthermore, FOXO1 function was required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PPARGC1. Insulin (176730) suppressed gluconeogenesis stimulated by PPARGC1, but coexpression of a mutant allele of FOXO1 insensitive to insulin completely reversed this suppression in hepatocytes or transgenic mice.Puigserver et al. (2003) concluded that FOXO1 and PPARGC1 interact in the execution of a program of powerful, insulin-regulated gluconeogenesis.
Nakae et al. (2003) found that a constitutively active mutant of Foxo1 prevented differentiation of a mouse preadipocyte cell line, while a dominant-negative mutant restored adipocyte differentiation of fibroblasts in insulin receptor (147670)-deficient mice. Foxo1 haploinsufficiency also protected mice from diet-induced diabetes.
Using adenovirus-mediated gene transfer to deliver FOXO1 cDNA to cultured hepatocytes and enterocytes,Altomonte et al. (2004) demonstrated that FOXO1 stimulated apolipoprotein C-III (APOC3;107720) expression and that this correlated with FOXO1 binding to the APOC3 promoter. Deletion or mutation of the FOXO1 binding site abolished the FOXO1-mediated stimulation and the APOC3 response to insulin. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia; in livers of diabetic NOD or db/db mice, Foxo1 expression was deregulated, culminating in significantly elevated production and skewed nuclear distribution of Foxo1.Altomonte et al. (2004) suggested that FOXO1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.
Giannakou et al. (2004) expressed Drosophila FOXO (dFOXO) in the adult body fat, which is the fly equivalent of the mammalian liver, and white adipose tissue. Induced expression of dFOXO in the fat body from the onset of adulthood increased life span and reduced fecundity of female flies by 20 to 50% and by 50%, respectively, and increased resistance to paraquat in females. No effect on life span was seen in male flies.Giannakou et al. (2004) noted that these and other data consistently implicated adipose tissue as important in mediating extension of life span by altering insulin/insulin-like growth factor (see147440) signaling in 3 model organisms: mouse, C. elegans, and Drosophila.Tatar (2005) commented that the results reported byGiannakou et al. (2004) did not show improved survival by induced expression of dFOXO but rather an excess of mortality among young control flies.Giannakou et al. (2005) replied thatTatar (2005) misanalyzed their data, and they stood by their results.
Hwangbo et al. (2004) demonstrated that dFOXO regulates the melanogastric agent when activated in the adult pericerebellar fat body. They further showed that this limited activation of dFOXO reduced expression of Drosophila in polypeptide DILP-2 synthesized in neurons and repressed endogenous insulin-dependent signaling in the peripheral fat body.Hwangbo et al. (2004) concluded that autonomous and nonautonomous roles of insulin signaling combine to control aging.
Kitamura et al. (2006) delivered adenovirus encoding a constitutively nuclear mutant Foxo1a to the hypothalamic arcuate nucleus of rodents and observed a loss of the ability of leptin (164160) to curtail food intake or to suppress expression of Agouti-related protein (AGRP;602311). Conversely, a transactivation-deficient Foxo1a mutant prevented induction of Agrp by fasting. Using reporter gene, gel shift, and immunoprecipitation assays,Kitamura et al. (2006) demonstrated that Foxo1a and Stat3 (102582) exerted opposing actions on the expression of Agrp and Pomc (176830) through transcriptional interference. Foxo1a promoted opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc.Kitamura et al. (2006) concluded that Foxo1a mediates the Agrp-dependent effects of leptin on food intake.
Liu et al. (2008) demonstrated that a fasting-inducible switch, consisting of the histone acetyltransferase p300 (602700) and the nutrient-sensing deacetylase sirtuin-1 (SIRT1;604479), maintains energy balance in mice through the sequential induction of CRTC2 (608972) and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, whichLiu et al. (2008) showed is also activated by dephosphorylation at ser89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at lys628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1;608067). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the SIRT1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator Ppar-gamma coactivator 1-alpha (PGC1-alpha;604517) by SIRT1 activators,Liu et al. (2008) concluded that their results illustrate how the exchange of 2 gluconeogenic regulators during fasting maintains energy balance.
In mice with deletion of the insulin receptor substrate genes Irs1 (147545) and Irs2 (600797),Cheng et al. (2009) observed increased hepatic expression of several Foxo1 target genes, including Hmox1 (141250), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Deletion of hepatic Foxo1 in mutant liver normalized the expression of Hmox1 and the NAD+/NADH ratio, reduced Ppargc1a acetylation, and restored mitochondrial oxidative metabolism and biogenesis.Cheng et al. (2009) concluded that FOXO1 integrates insulin signaling with mitochondrial function and inhibition of FOXO1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.
Demontis and Perrimon (2010) showed that signaling through the transcription factor Foxo and its target Thor/4Ebp (see602223) regulated aging in Drosophila muscle. Increased activity of Foxo and 4Ebp delayed age-related muscle weakness and preserved muscle function, at least in part, by promoting basal activity of the autophagy/lysosome system for the elimination of deleterious protein aggregates. Foxo/4Ebp signaling in muscle also decreased feeding behavior and the release of insulin, which in turn delayed age-related accumulation of protein aggregates in other tissues, increasing life span.
Talchai et al. (2012) showed that, unexpectedly, somatic ablation of Foxo1 in Neurog3 (604882)-positive (Neurog3+) enteroendocrine progenitor cells gives rise to gut insulin-positive cells that express markers of mature beta cells and secrete bioactive insulin as well as C peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut insulin-positive cells arise cell autonomously from Foxo1-deficient cells. Inducible Fox1 ablation in adult mice also resulted in the generation of gut insulin-positive cells. Following ablation by the beta-cell toxin streptozotocin, gut insulin-positive cells regenerated and produced insulin, reversing hyperglycemia in mice.Talchai et al. (2012) concluded that their data indicated that Neurog3+ enteroendocrine progenitors require active Foxo1 to prevent differentiation into insulin-positive cells, and suggested that Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.
Role in Angiogenesis
By examining FOXO transcription factors involved in the angiogenic activity of human umbilical vein endothelial cells (HUVECs),Potente et al. (2005) found that FOXO1 and FOXO3A were the most abundant FOXO genes expressed in mature endothelial cells. Overexpression of constitutively active FOXO1 and FOXO3A, but not FOXO4 (MLLT7), significantly inhibited endothelial cell migration and tube formation in vitro. Silencing of either FOXO1 or FOXO3A gene expression led to a profound increase in the migratory and sprout-forming capacity of HUVECs. Gene expression profiling showed that FOXO1 and FOXO3A specifically regulate a nonredundant but overlapping set of angiogenesis- and vascular remodeling-related genes. Whereas angiopoietin-2 (601922) was exclusively regulated by FOXO1, ENOS (NOS3;163729), which is essential for postnatal neovascularization, was regulated by FOXO1 and FOXO3A. Constitutively active FOXO1 and FOXO3A repressed ENOS protein expression and bound to the ENOS promoter. In vivo, Foxo3a deficiency in mice increased Enos expression and enhanced postnatal vessel formation and maturation.
Wilhelm et al. (2016) reported that FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in endothelial cells. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in endothelial cell proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching.Wilhelm et al. (2016) found that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signaling by MYC (190080), a powerful driver of anabolic metabolism and growth. MYC ablation impairs the glycolysis, mitochondrial function, and proliferation of endothelial cells, while its endothelial cell-specific overexpression fuels these processes. Moreover, restoration of MYC signaling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behavior.Wilhelm et al. (2016) concluded that their findings identified FOXO1 as a critical rheostat of vascular expansion and defined the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation.
Role in Osteogenesis
Teixeira et al. (2010) found that treatment of mouse mesenchymal cells with the osteogenic stimulants BMP2 (112261), SHH (600725), or PTHRP (PTHLH;168470) induced expression of Foxo1 and the osteoblastic differentiation markers Runx2 (600211), Alp (ALPL;171760), and osteocalcin (BGLAP;112260). Similar results were found in primary human mesenchymal cells stimulated with dexamethasone. Silencing of Foxo1 in mesenchymal cells reduced the upregulation of osteoblastic markers in response to BMP2 treatment. In contrast, overexpression of Foxo1 upregulated expression of Runx2, Alp, and osteocalcin in the absence of BMP2 stimulation. Knockdown studies confirmed the involvement of Foxo1 in Runx2 expression and in bone development in embryonic mice and in ex vivo bone cultures. Sequence analysis revealed 3 putative Foxo1-binding sites in the Runx2 promoter, and binding was confirmed by coimmunoprecipitation analysis. RT-PCR, reporter gene assays, and chromatin immunoprecipitation assays confirmed direct functional control of Runx2 expression by Foxo1.
Role in T-Cell Regulation
Ouyang et al. (2012) demonstrated that Foxo1 is a pivotal regulator of regulatory T (T(reg)) cell function. T(reg) cells express high amounts of Foxo1 and display reduced T cell receptor-induced Akt (164730) activation, Foxo1 phosphorylation, and Foxo1 nuclear exclusion. Mice with T(reg)-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3 (300292)-deficient mice, but without the loss of T(reg) cells. Genomewide analysis of Foxo1 binding sites revealed approximately 300 Foxo1-bound target genes, including the proinflammatory cytokine Ifng (147570), that do not seem to be directly regulated by Foxp3.Ouyang et al. (2012) concluded that the evolutionarily ancient Akt-Foxo1 signaling module controls a novel genetic program indispensable for T(reg) cell function.
Luo et al. (2016) showed that the transcription factor Foxo1, previously demonstrated to promote T(reg) cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting activated T(reg) (aT(reg))-cell-mediated immune tolerance in mice.Luo et al. (2016) found that aT(reg) cells turned over at a slower rate than resting T(reg) (rT(reg)) cells, but were not locally maintained in tissues. aT(reg) cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization, and enhanced phosphorylation at the Akt sites. T(reg) cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules and impeded T(reg) cell homing to nonlymphoid organs, causing CD8+ T-cell-mediated autoimmune diseases. Compared to T(reg) cells from healthy tissues, tumor-infiltrating T(reg) cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated T(reg) cells, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aT(reg) cells that have a crucial function in suppressing CD8+ T-cell responses, and the Foxo signaling pathway in T(reg) cells can be titrated to break tumor immune tolerance preferentially.
Role in Embryonic Stem Cell Pluripotency
Zhang et al. (2011) found that FOXO1 expression was essential for maintenance of pluripotency in human and mouse embryonic stem cells (ESCs). Nuclear FOXO1 was highly expressed in undifferentiated human ESCs and was downregulated during embryoid body formation and commitment to mesoderm and hematopoietic cells. FOXO1 directly regulated expression of OCT4 (POU5F1;164177) and SOX2 (184429), which are required for maintenance of pluripotency.
FKHR/PAX3 Fusion Protein
Galili et al. (1993) determined that the translocation t(2;13)(q35;q14) in alveolar rhabdomyosarcoma (268220) results in a PAX3 (606597)/FKHR chimeric protein. The 837-amino acid PAX3/FKHR chimeric protein contains the intact PAX3 DNA-binding domain, the C-terminal half of the FKHR forkhead domain, and the C-terminal FKHR region. It had an apparent molecular mass of 97 kD by SDS-PAGE.
Fredericks et al. (1995) demonstrated expression of a 97-kD PAX3/FKHR fusion protein in a t(2;13)-positive rhabdomyosarcoma cell line and verified that a single polypeptide contained epitopes derived from each protein. The fusion protein was localized to the nucleus in these cells, as was wildtype PAX3 in cells lacking the translocation. They found that DNA binding of the fusion protein was significantly impaired relative to that of PAX3 despite the fact that the 2 proteins had identical PAX DNA-binding domains. However, the fusion protein was a much more potent transcriptional activator than PAX3. Thus, the fusion protein may function as an oncogenic transcription factor by enhancing activation of normal PAX3 target genes.
Sublett et al. (1995) found that the PAX3/FKHR hybrid protein binds DNA in vitro in a sequence-specific manner and transactivates the expression of artificial reporter genes, suggesting that its aberrant expression could subvert the transcriptional programs that normally control the growth, differentiation, and survival of primitive myogenic precursors in vivo.
Using a retroviral vector,Scheidler et al. (1996) introduced the PAX3/FKHR fusion gene into chicken embryo fibroblasts. Expression of the PAX3/FKHR protein in these cells led to transformation: the cells became enlarged, grew tightly packed and in multiple layers, and acquired the ability for anchorage-independent growth.
The PAX3/FKHR chimeric gene possesses transforming properties. To investigate the actions of these transcription factors,Khan et al. (1999) introduced both PAX3 and PAX3/FKHR into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a mouse cDNA microarray containing 2,225 elements. They found that PAX3/FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors Myod (159970), myogenin (159980), Six1 (601205), and Slug (602150), as well as a battery of genes involved in several aspects of muscle function.
Roeb et al. (2007) found that myoblasts from transgenic mice expressing PAX3/FOXO1 under control of the PAX3 promoter were unable to complete myogenic differentiation because of an inability to upregulate p57(Kip2) (CDKN1C;600856) transcription. This defect was caused by reduced levels of the transcriptional activator Egr1 (128990) resulting from a direct, destabilizing interaction with PAX3/FOXO1. Neither PAX3 nor FOXO1 shared the ability to regulate p57(Kip2) transcription.
The translocation t(2;13)(q35;q14) is frequently found in alveolar rhabdomyosarcoma (268220).Barr et al. (1993) determined that PAX3 (606597) was affected by this t(2;13) in alveolar rhabdomyosarcoma.Galili et al. (1993) identified FKHR as the chromosome 13 gene fused with PAX3 in t(2;13)(q35;q14). The translocation breakpoints occurred within an intron downstream of the paired box- and homeodomain-encoding regions of PAX3 and within an intron in the forkhead domain-encoding region of FKHR. RT-PCR detected the 5-prime-PAX3/3-prime-FKHR transcript from the der13 chromosome in all 7 t(2;13)-containing rhabdomyosarcoma cell lines examined. The shorter reciprocal transcript from the der2 chromosome was detected in 6 of the 7 t(2;13)-containing cell lines. The 837-amino acid PAX3/FKHR chimeric protein contains the intact PAX3 DNA-binding domain, the C-terminal half of the FKHR forkhead domain, and the C-terminal FKHR region. It had an apparent molecular mass of 97 kD by SDS-PAGE.
In a review of 28 published cases of alveolar rhabdomyosarcoma with cytogenetic studies,Whang-Peng et al. (1992) found the characteristic t(2;13) translocation in 64%; in 18% of cases they found a variant t(1;13)(p36;q14) translocation that was subsequently shown to result in fusion of the FKHR gene with the PAX7 gene (167410) on chromosome 1.
Davis and Barr (1997) demonstrated that in both the t(2;13) and the variant t(1;13) translocations, which generate PAX3/FKHR and PAX7/FKHR fusion proteins, respectively, there is overexpression of the fusion product in addition to functional alterations. In the t(2;13) translocation, transcription of PAX3/FKHR is increased relative to wildtype PAX3 by a copy number-independent process. In contrast, PAX7/FKHR overexpression results from fusion gene amplification.
FOXO3A (602681) has been linked to human longevity in Japanese, German, and Italian populations.Li et al. (2009) tested the genetic contribution of FOXO1A and FOXO3A to longevity in the Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were genotyped in 1,817 centenarians and younger individuals. Two SNPs of FOXO1A were associated with longevity in women (P = 0.01-0.005), whereas all 3 SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was not associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 and 1.38 (P = 0.0033 and 0.0063, respectively). The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (P = 0.0014); CGT: OR (95% CI) = 1.48 (P = 0.0035)] and in women [GTC: OR (95% CI) = 0.75 (P = 0.0094); CGT: OR (95% CI) = 1.47 (P = 0.0009)]. The association of FOXO1A with female longevity was replicated in 350 centenarians and 350 younger individuals from a different geographic location. The authors concluded that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by gender.
Anderson et al. (2001) produced transgenic mice in which Pax3-Fkhr expression was driven by mouse Pax3 promoter/enhancer sequences. Five independent lines expressed Pax3-Fkhr in the dorsal neural tube and lateral dermomyotome. Each line exhibited phenotypes that correlated with Pax3-Fkhr expression levels and predominantly involved pigmentary disturbances of the abdomen, hind paws, and tail, with additional neurologic-related alterations. Phenotypic severity could be increased by reducing Pax3 levels through matings with Pax3-defective Splotch mice, and interference between Pax3 and Pax3-Fkhr was apparent in transcription reporter assays. These data suggested that the tumor-associated PAX3-FKHR fusion protein interferes with normal PAX3 developmental functions as a prelude to transformation.
Nakae et al. (2002) investigated the mechanism of beta-cell failure in type 2 diabetes (125852). In mice, they identified Foxo1 as a component of insulin signaling in liver, adipose tissue, and beta-cells. Through a genetic analysis with gain- and loss-of-function alleles, they showed that the protein Foxo1 controls 2 important processes in the pathogenesis of type 2 diabetes: hepatic glucose production and beta-cell compensation of insulin resistance. Haploinsufficiency of the Foxo1 gene restored insulin sensitivity and rescued the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenic genes and increasing adipocyte expression of insulin-sensitizing genes. Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells resulted in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased expression of insulin promoter factor-1 (IPF1;600733), also known as Pdx1. The data indicated that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes, and pancreatic beta-cells. Impaired insulin signaling to Foxo1 provides a unifying mechanism for the common metabolic abnormalities of type 2 diabetes.
Lagutina et al. (2002) generated mice carrying a Pax3-Fkhr knockin allele. Despite low expression of this allele, heterozygous offspring of Pax3-Fkhr chimeric mice showed developmental abnormalities, including intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. Heterozygotes also displayed malformations of some, but not all, hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy.Lagutina et al. (2002) concluded that the Pax2-Fkhr allele causes lethal developmental defects in knockin mice but is insufficient to cause muscle tumors.
Relaix et al. (2003) found that mice expressing Fkhr/Pax3 displayed developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events resulted from overexpression of Met (164860), leading to constitutive activation of Met signaling. The gain-of-function phenotype was also characterized by overactivation of MyoD.
The C. elegans transcription factor hsf1 (140580) regulates the heat-shock response and influences aging. Reducing hsf1 activity accelerates tissue aging and shortens life span;Hsu et al. (2003) showed that hsf1 overexpression extends life span.Hsu et al. (2003) found that hsf1, like the transcription factor daf16, whose human homologs include FOXO1, FOXO3A (602681), and FOXO4 (MLLT7;300033), is required for daf2-insulin/Igf1 receptor (147370) mutations to extend life span.Hsu et al. (2003) concluded that this is because hsf1 and daf16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
Kamei et al. (2004) found that transgenic mice with specific overexpression of human FOXO1A in skeletal muscle were smaller with a decreased lean muscle mass and exhibited impaired spontaneous activity on the running wheel test compared to controls. The skeletal muscle of the transgenic mice was pale and showed both atrophy and loss of type I fibers without morphologic abnormalities. Microarray, Northern blot, and Western blot analysis showed a decreased expression of many genes related to structural proteins of type I muscle fibers. Metabolically, the transgenic mice had impaired glucose tolerance and insulin resistance.Kamei et al. (2004) concluded that FOXO1A is involved in the negative regulation of skeletal muscle mass and that upregulation of the protein may lead to impaired muscle function.
Paik et al. (2007) generated null and conditional alleles for Foxo1, Foxo3, and Foxo4 to assess their role in cancer in vivo. Mice with germline or somatic deletion of up to 5 Foxo alleles, including Foxo1 +/- Foxo3 -/- Foxo4 -/- mice, had only modest neoplastic phenotypes. In contrast, broad somatic deletion of Foxo1, Foxo3, and Foxo4 engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas. Transcriptome and promoter analyses of differentially affected endothelium identified direct Foxo targets and revealed that Foxo regulation of these targets in vivo was highly context specific, even in the same cell type. Functional studies validated Spry2 (602466) and Pbx1 (176310), among others, as Foxo-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
Tothova et al. (2007) conditionally deleted Foxo1, Foxo3, and Foxo4 in the adult mouse hematopoietic system. Foxo-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative/Sca1-positive/Kit (164920)-positive compartment containing short- and long-term hematopoietic stem cell (HSC) populations. Foxo-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSCs. There was a marked context-dependent increase in reactive oxygen species (ROS) in Foxo-deficient HSCs compared with wildtype HSCs that correlated with changes in genes encoding regulators of ROS. In vivo treatment with an antioxidative agent resulted in reversion of the Foxo-deficient phenotype.Tothova et al. (2007) concluded that FOXO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment.
Biddinger et al. (2008) generated liver-specific Insr (147670)-knockout (LIRKO) mice and observed a marked predisposition to cholesterol gallstone formation that was due in part to disinhibition of Foxo1, which increased expression of the biliary cholesterol transporters Abcg5 (605459) and Abcg8 (605460) and resulted in an increase in biliary cholesterol secretion.
Plum et al. (2009) generated mice with POMC (176830)-neuron-specific ablation of Foxo1 and observed an increase in Cpe (114855) expression that resulted in selective increase of alpha-Msh and beta-endorphin, which are the products of CPE-dependent processing of POMC. This neuropeptide profile was associated with decreased food intake and normal energy expenditure in the POMC-Foxo1 -/- mice. CPE expression was downregulated by diet-induced obesity, and Foxo1 deletion offset that decrease, protecting against weight gain. Leptin (164160) curtailed food intake more markedly in POMC-Foxo1 -/- mice than in wildtype mice, consistent with increased sensitivity to leptin; unexpectedly, there was also a near doubling of leptin levels in the POMC-Foxo1 -/- mice. Moderate Cpe overexpression in the arcuate nucleus phenocopied features seen in the POMC-Foxo1 -/- mice.Plum et al. (2009) concluded that Foxo1 ablation in hypothalamic POMC neurons reduces food intake without concurrently decreasing energy expenditure or leptin levels, and that this effect is mediated by Cpe; they stated that this was the first time that hypophagia and reduced body weight had been uncoupled from energy expenditure and leptin levels.
Ouyang et al. (2009) generated mice with T cell-specific deletion of Foxo1 and found that these mice could overcome embryonic lethality associated with germline deletion. Flow cytometric analysis detected no changes in thymic T-cell development. However, peripheral T cells lacking Foxo1 exhibited an activated phenotype, effector cell differentiation, and autoantibody induction, with reduced numbers of naive T cells. Gene expression profiling identified Il7r (146661) as a target of Foxo1. Cell surface expression of Il7r was reduced in Foxo1 -/- T cells, and cell survival was not enhanced by Il7 (146660) treatment. Bone marrow chimera experiments revealed that diminished Il7r expression was a consequence of Foxo1 deficiency.Ouyang et al. (2009) concluded that FOXO1 has a critical role in T-cell tolerance and in naive T-cell homeostasis through induction of IL7R expression.
Ren et al. (2012) found that ablation of Foxo1 specifically in Agrp-positive hypothalamic neurons resulted in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to leptin and insulin in mice. Quantitative PCR and microarray analysis showed that Gpr17 (603071) was highly expressed in Agrp-positive mouse neurons and that Gpr17 expression increased during fasting. Gpr17 expression was decreased in Foxo1-deficient Agrp-positive neurons. Chromatin immunoprecipitation analysis confirmed that Foxo1 bound the Gpr17 promoter.Ren et al. (2012) concluded that downregulation of Gpr17, at least in part, mediates the anorexigenic phenotype of Foxo1-deficient Agrp-positive neurons.
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Modur, V., Nagarajan, R., Evers, B. M., Milbrandt, J.FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression: implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277: 47928-47937, 2002. [PubMed:12351634,related citations] [Full Text]
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Nakae, J., Kitamura, T., Kitamura, Y., Biggs, W. H., III, Arden, K. C., Accili, D.The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4: 119-129, 2003. [PubMed:12530968,related citations] [Full Text]
Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., Sellers, W. R.Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Molec. Cell. Biol. 20: 8969-8982, 2000. [PubMed:11073996,images,related citations] [Full Text]
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Plum, L., Lin, H. V., Dutia, R., Tanaka, J., Aizawa, K. S., Matsumoto, M., Kim, A. J., Cawley, N. X., Paik, J.-H., Loh, Y. P., DePinho, R. A., Wardlaw, S. L., Accili, D.The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nature Med. 15: 1195-1201, 2009. [PubMed:19767734,images,related citations] [Full Text]
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Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: FOXO1
Cytogenetic location: 13q14.11 Genomic coordinates(GRCh38) : 13:40,555,667-40,666,641(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 13q14.11 | Rhabdomyosarcoma, alveolar | 268220 | Somatic mutation | 3 |
By searching for genes in a region of chromosome 13 involved in a translocation causing alveolar rhabdomyosarcoma (268220), followed by sequencing overlapping cDNA clones from several libraries, Galili et al. (1993) obtained full-length FOXO1A, which they called FKHR. The deduced 655-amino acid protein has an alanine-rich region, a proline-rich region with characteristics of an SH3-binding site, and a DNA-binding forkhead domain of about 100 amino acids in its N-terminal half. Northern blot analysis detected a 6.5-kb transcript in all normal adult tissues examined, as well as in lymphoblasts and fibroblasts. Immunoprecipitated FOXO1A had an apparent molecular mass of 56 kD by SDS-PAGE.
Using RT-PCR and immunohistochemical analysis of mouse embryos at embryonic day 15.5, Teixeira et al. (2010) detected Foxo1 mRNA and protein expression in brain, tongue, liver, and cartilage. Highest expression was in areas of intramembranous bone formation, such as calvaria, and endochondral bone formation, such as diaphysis of long bones.
Galili et al. (1993) determined that the 5-prime upstream region of the FOXO1A gene includes a CpG island.
Galili et al. (1993) determined that the FOXO1A gene maps to chromosome 13q14.
Anderson et al. (1998) identified a processed pseudogene that is similar to FOXO1A and maps to chromosome 5q35.2-q35.3.
Role in Cell Cycle Regulation and Apoptosis
Medema et al. (2000) demonstrated that overexpression of the forkhead transcription factors FKHR, AFX (MLLT7; 300033), or FKHRL1 (FOXO3A; 602681) caused growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumor suppressor PTEN (601728). Medema et al. (2000) demonstrated that AFX transcriptionally activates p27(KIP1), resulting in increased protein levels, and concluded that AFX-like proteins are involved in cell cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.
By analyzing PTEN-deficient tumor cell lines, Nakamura et al. (2000) determined that PTEN deficiency leads to aberrant localization of FKHR to the cytoplasm. Restoration of PTEN expression restored FKHR to the nucleus and restored transcriptional activation. Nakamura et al. (2000) also found evidence that FKHR is an effector of PTEN activation, in that FKHR induced apoptosis in cells that undergo PTEN-mediated apoptosis, and FKHR mediated G1 arrest in cells that undergo PTEN-mediated cell cycle arrest.
Modur et al. (2002) found that both FKHR and FKHRL1 were highly expressed in normal prostate. They also noted that, in PTEN-deficient prostate carcinoma cell lines, FKHR and FKHRL1 were cytoplasmically sequestered and inactive, and expression of TRAIL (603598), a proapoptotic effector, was decreased. Modur et al. (2002) determined that TRAIL is a direct target of FKHRL1, and they hypothesized that the loss of PTEN contributes to increased tumor cell survival through decreased transcriptional activity of FKHR and FKHRL1 followed by decreased TRAIL expression and apoptosis.
Huang et al. (2006) found that CDK2 (116953) specifically phosphorylated FOXO1 at ser249 in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of FOXO1. This phosphorylation was abrogated upon DNA damage through the cell cycle checkpoint pathway that is dependent on the protein kinases CHK1 (603078) and CHK2 (604373). Moreover, silencing of FOXO1 by small interfering RNA diminished DNA damage-induced death in both p53 (191170)-deficient and p53-proficient cells. This effect was reversed by restored expression of FOXO1 in a manner depending on phosphorylation of ser249. Huang et al. (2006) concluded that functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage.
Yuan et al. (2008) found that CDK1 (116940) phosphorylated the transcription factor FOXO1 at serine-249 in vitro and in vivo. The phosphorylation of FOXO1 at serine-249 disrupted FOXO1 binding with 14-3-3 (see 601289) proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, CDK1 induced FOXO1 serine-249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk; 602098). Yuan et al. (2008) concluded that their findings defined a conserved signaling link between CDK1 and FOXO1 that may have a key role in diverse biologic processes including the degeneration of postmitotic neurons.
By Northern blot analysis, Berry et al. (2008) found that FOXC1 (601090) induced the expression of the apoptosis regulator FOXO1A about 13-fold. The promoter regions of zebrafish and human FOXO1A contain consensus FOXC1 binding sites; chromatin immunoprecipitation and reporter gene assays confirmed that FOXC1 bound these sites and activated the FOXO1A promoter. Knockdown of FOXC1 in human trabecular meshwork cells reduced FOXO1A expression and increased cell death in response to oxidative stress. Morpholino-mediated knockdown of Foxo1a in zebrafish embryos resulted in increased cell death in the developing eye.
Using bioinformatics analysis, McLoughlin et al. (2014) identified a conserved putative MIR183 (611608) target site in the 3-prime UTR of FOXO1 mRNA. They also identified a human-specific MIR183 target site in the 3-prime UTR of human FOXO1 that was created by a single nucleotide change relative to mouse and chimpanzee Foxo1. Reporter gene assays and site-directed mutagenesis studies revealed that synthetic MIR183 downregulated expression of FOXO1 in a dose-dependent manner from the human-specific MIR183 target site, but not the conserved MIR183 target site. Overexpression of pre-MIR183 downregulated FOXO1 expression and increased invasive potential in human ONS-76 medulloblastoma cells, but not in mouse C17-2 cerebellar stem cells. Overexpression of pre-MIR183 decreased cell proliferation in both ONS-76 and C17-2 cells, whereas protection of the MIR183 target site in the 3-prime UTR of FOXO1 rescued proliferation in ONS-76 cells, but not in C17-2 cells, suggesting that MIR183 targets other than Foxo1 contribute to proliferation in mouse cells.
Role in Insulin Signaling and Energy Metabolism
Using wildtype and mutant alleles of FOXO1, Puigserver et al. (2003) demonstrated that PPARGC1 (604517) binds and coactivates FOXO1 in a manner inhibited by AKT-mediated phosphorylation. Furthermore, FOXO1 function was required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PPARGC1. Insulin (176730) suppressed gluconeogenesis stimulated by PPARGC1, but coexpression of a mutant allele of FOXO1 insensitive to insulin completely reversed this suppression in hepatocytes or transgenic mice. Puigserver et al. (2003) concluded that FOXO1 and PPARGC1 interact in the execution of a program of powerful, insulin-regulated gluconeogenesis.
Nakae et al. (2003) found that a constitutively active mutant of Foxo1 prevented differentiation of a mouse preadipocyte cell line, while a dominant-negative mutant restored adipocyte differentiation of fibroblasts in insulin receptor (147670)-deficient mice. Foxo1 haploinsufficiency also protected mice from diet-induced diabetes.
Using adenovirus-mediated gene transfer to deliver FOXO1 cDNA to cultured hepatocytes and enterocytes, Altomonte et al. (2004) demonstrated that FOXO1 stimulated apolipoprotein C-III (APOC3; 107720) expression and that this correlated with FOXO1 binding to the APOC3 promoter. Deletion or mutation of the FOXO1 binding site abolished the FOXO1-mediated stimulation and the APOC3 response to insulin. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia; in livers of diabetic NOD or db/db mice, Foxo1 expression was deregulated, culminating in significantly elevated production and skewed nuclear distribution of Foxo1. Altomonte et al. (2004) suggested that FOXO1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.
Giannakou et al. (2004) expressed Drosophila FOXO (dFOXO) in the adult body fat, which is the fly equivalent of the mammalian liver, and white adipose tissue. Induced expression of dFOXO in the fat body from the onset of adulthood increased life span and reduced fecundity of female flies by 20 to 50% and by 50%, respectively, and increased resistance to paraquat in females. No effect on life span was seen in male flies. Giannakou et al. (2004) noted that these and other data consistently implicated adipose tissue as important in mediating extension of life span by altering insulin/insulin-like growth factor (see 147440) signaling in 3 model organisms: mouse, C. elegans, and Drosophila. Tatar (2005) commented that the results reported by Giannakou et al. (2004) did not show improved survival by induced expression of dFOXO but rather an excess of mortality among young control flies. Giannakou et al. (2005) replied that Tatar (2005) misanalyzed their data, and they stood by their results.
Hwangbo et al. (2004) demonstrated that dFOXO regulates the melanogastric agent when activated in the adult pericerebellar fat body. They further showed that this limited activation of dFOXO reduced expression of Drosophila in polypeptide DILP-2 synthesized in neurons and repressed endogenous insulin-dependent signaling in the peripheral fat body. Hwangbo et al. (2004) concluded that autonomous and nonautonomous roles of insulin signaling combine to control aging.
Kitamura et al. (2006) delivered adenovirus encoding a constitutively nuclear mutant Foxo1a to the hypothalamic arcuate nucleus of rodents and observed a loss of the ability of leptin (164160) to curtail food intake or to suppress expression of Agouti-related protein (AGRP; 602311). Conversely, a transactivation-deficient Foxo1a mutant prevented induction of Agrp by fasting. Using reporter gene, gel shift, and immunoprecipitation assays, Kitamura et al. (2006) demonstrated that Foxo1a and Stat3 (102582) exerted opposing actions on the expression of Agrp and Pomc (176830) through transcriptional interference. Foxo1a promoted opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Kitamura et al. (2006) concluded that Foxo1a mediates the Agrp-dependent effects of leptin on food intake.
Liu et al. (2008) demonstrated that a fasting-inducible switch, consisting of the histone acetyltransferase p300 (602700) and the nutrient-sensing deacetylase sirtuin-1 (SIRT1; 604479), maintains energy balance in mice through the sequential induction of CRTC2 (608972) and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which Liu et al. (2008) showed is also activated by dephosphorylation at ser89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at lys628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1; 608067). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the SIRT1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator Ppar-gamma coactivator 1-alpha (PGC1-alpha; 604517) by SIRT1 activators, Liu et al. (2008) concluded that their results illustrate how the exchange of 2 gluconeogenic regulators during fasting maintains energy balance.
In mice with deletion of the insulin receptor substrate genes Irs1 (147545) and Irs2 (600797), Cheng et al. (2009) observed increased hepatic expression of several Foxo1 target genes, including Hmox1 (141250), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Deletion of hepatic Foxo1 in mutant liver normalized the expression of Hmox1 and the NAD+/NADH ratio, reduced Ppargc1a acetylation, and restored mitochondrial oxidative metabolism and biogenesis. Cheng et al. (2009) concluded that FOXO1 integrates insulin signaling with mitochondrial function and inhibition of FOXO1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.
Demontis and Perrimon (2010) showed that signaling through the transcription factor Foxo and its target Thor/4Ebp (see 602223) regulated aging in Drosophila muscle. Increased activity of Foxo and 4Ebp delayed age-related muscle weakness and preserved muscle function, at least in part, by promoting basal activity of the autophagy/lysosome system for the elimination of deleterious protein aggregates. Foxo/4Ebp signaling in muscle also decreased feeding behavior and the release of insulin, which in turn delayed age-related accumulation of protein aggregates in other tissues, increasing life span.
Talchai et al. (2012) showed that, unexpectedly, somatic ablation of Foxo1 in Neurog3 (604882)-positive (Neurog3+) enteroendocrine progenitor cells gives rise to gut insulin-positive cells that express markers of mature beta cells and secrete bioactive insulin as well as C peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut insulin-positive cells arise cell autonomously from Foxo1-deficient cells. Inducible Fox1 ablation in adult mice also resulted in the generation of gut insulin-positive cells. Following ablation by the beta-cell toxin streptozotocin, gut insulin-positive cells regenerated and produced insulin, reversing hyperglycemia in mice. Talchai et al. (2012) concluded that their data indicated that Neurog3+ enteroendocrine progenitors require active Foxo1 to prevent differentiation into insulin-positive cells, and suggested that Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.
Role in Angiogenesis
By examining FOXO transcription factors involved in the angiogenic activity of human umbilical vein endothelial cells (HUVECs), Potente et al. (2005) found that FOXO1 and FOXO3A were the most abundant FOXO genes expressed in mature endothelial cells. Overexpression of constitutively active FOXO1 and FOXO3A, but not FOXO4 (MLLT7), significantly inhibited endothelial cell migration and tube formation in vitro. Silencing of either FOXO1 or FOXO3A gene expression led to a profound increase in the migratory and sprout-forming capacity of HUVECs. Gene expression profiling showed that FOXO1 and FOXO3A specifically regulate a nonredundant but overlapping set of angiogenesis- and vascular remodeling-related genes. Whereas angiopoietin-2 (601922) was exclusively regulated by FOXO1, ENOS (NOS3; 163729), which is essential for postnatal neovascularization, was regulated by FOXO1 and FOXO3A. Constitutively active FOXO1 and FOXO3A repressed ENOS protein expression and bound to the ENOS promoter. In vivo, Foxo3a deficiency in mice increased Enos expression and enhanced postnatal vessel formation and maturation.
Wilhelm et al. (2016) reported that FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in endothelial cells. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in endothelial cell proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. Wilhelm et al. (2016) found that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signaling by MYC (190080), a powerful driver of anabolic metabolism and growth. MYC ablation impairs the glycolysis, mitochondrial function, and proliferation of endothelial cells, while its endothelial cell-specific overexpression fuels these processes. Moreover, restoration of MYC signaling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behavior. Wilhelm et al. (2016) concluded that their findings identified FOXO1 as a critical rheostat of vascular expansion and defined the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation.
Role in Osteogenesis
Teixeira et al. (2010) found that treatment of mouse mesenchymal cells with the osteogenic stimulants BMP2 (112261), SHH (600725), or PTHRP (PTHLH; 168470) induced expression of Foxo1 and the osteoblastic differentiation markers Runx2 (600211), Alp (ALPL; 171760), and osteocalcin (BGLAP; 112260). Similar results were found in primary human mesenchymal cells stimulated with dexamethasone. Silencing of Foxo1 in mesenchymal cells reduced the upregulation of osteoblastic markers in response to BMP2 treatment. In contrast, overexpression of Foxo1 upregulated expression of Runx2, Alp, and osteocalcin in the absence of BMP2 stimulation. Knockdown studies confirmed the involvement of Foxo1 in Runx2 expression and in bone development in embryonic mice and in ex vivo bone cultures. Sequence analysis revealed 3 putative Foxo1-binding sites in the Runx2 promoter, and binding was confirmed by coimmunoprecipitation analysis. RT-PCR, reporter gene assays, and chromatin immunoprecipitation assays confirmed direct functional control of Runx2 expression by Foxo1.
Role in T-Cell Regulation
Ouyang et al. (2012) demonstrated that Foxo1 is a pivotal regulator of regulatory T (T(reg)) cell function. T(reg) cells express high amounts of Foxo1 and display reduced T cell receptor-induced Akt (164730) activation, Foxo1 phosphorylation, and Foxo1 nuclear exclusion. Mice with T(reg)-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3 (300292)-deficient mice, but without the loss of T(reg) cells. Genomewide analysis of Foxo1 binding sites revealed approximately 300 Foxo1-bound target genes, including the proinflammatory cytokine Ifng (147570), that do not seem to be directly regulated by Foxp3. Ouyang et al. (2012) concluded that the evolutionarily ancient Akt-Foxo1 signaling module controls a novel genetic program indispensable for T(reg) cell function.
Luo et al. (2016) showed that the transcription factor Foxo1, previously demonstrated to promote T(reg) cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting activated T(reg) (aT(reg))-cell-mediated immune tolerance in mice. Luo et al. (2016) found that aT(reg) cells turned over at a slower rate than resting T(reg) (rT(reg)) cells, but were not locally maintained in tissues. aT(reg) cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization, and enhanced phosphorylation at the Akt sites. T(reg) cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules and impeded T(reg) cell homing to nonlymphoid organs, causing CD8+ T-cell-mediated autoimmune diseases. Compared to T(reg) cells from healthy tissues, tumor-infiltrating T(reg) cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated T(reg) cells, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aT(reg) cells that have a crucial function in suppressing CD8+ T-cell responses, and the Foxo signaling pathway in T(reg) cells can be titrated to break tumor immune tolerance preferentially.
Role in Embryonic Stem Cell Pluripotency
Zhang et al. (2011) found that FOXO1 expression was essential for maintenance of pluripotency in human and mouse embryonic stem cells (ESCs). Nuclear FOXO1 was highly expressed in undifferentiated human ESCs and was downregulated during embryoid body formation and commitment to mesoderm and hematopoietic cells. FOXO1 directly regulated expression of OCT4 (POU5F1; 164177) and SOX2 (184429), which are required for maintenance of pluripotency.
FKHR/PAX3 Fusion Protein
Galili et al. (1993) determined that the translocation t(2;13)(q35;q14) in alveolar rhabdomyosarcoma (268220) results in a PAX3 (606597)/FKHR chimeric protein. The 837-amino acid PAX3/FKHR chimeric protein contains the intact PAX3 DNA-binding domain, the C-terminal half of the FKHR forkhead domain, and the C-terminal FKHR region. It had an apparent molecular mass of 97 kD by SDS-PAGE.
Fredericks et al. (1995) demonstrated expression of a 97-kD PAX3/FKHR fusion protein in a t(2;13)-positive rhabdomyosarcoma cell line and verified that a single polypeptide contained epitopes derived from each protein. The fusion protein was localized to the nucleus in these cells, as was wildtype PAX3 in cells lacking the translocation. They found that DNA binding of the fusion protein was significantly impaired relative to that of PAX3 despite the fact that the 2 proteins had identical PAX DNA-binding domains. However, the fusion protein was a much more potent transcriptional activator than PAX3. Thus, the fusion protein may function as an oncogenic transcription factor by enhancing activation of normal PAX3 target genes.
Sublett et al. (1995) found that the PAX3/FKHR hybrid protein binds DNA in vitro in a sequence-specific manner and transactivates the expression of artificial reporter genes, suggesting that its aberrant expression could subvert the transcriptional programs that normally control the growth, differentiation, and survival of primitive myogenic precursors in vivo.
Using a retroviral vector, Scheidler et al. (1996) introduced the PAX3/FKHR fusion gene into chicken embryo fibroblasts. Expression of the PAX3/FKHR protein in these cells led to transformation: the cells became enlarged, grew tightly packed and in multiple layers, and acquired the ability for anchorage-independent growth.
The PAX3/FKHR chimeric gene possesses transforming properties. To investigate the actions of these transcription factors, Khan et al. (1999) introduced both PAX3 and PAX3/FKHR into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a mouse cDNA microarray containing 2,225 elements. They found that PAX3/FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors Myod (159970), myogenin (159980), Six1 (601205), and Slug (602150), as well as a battery of genes involved in several aspects of muscle function.
Roeb et al. (2007) found that myoblasts from transgenic mice expressing PAX3/FOXO1 under control of the PAX3 promoter were unable to complete myogenic differentiation because of an inability to upregulate p57(Kip2) (CDKN1C; 600856) transcription. This defect was caused by reduced levels of the transcriptional activator Egr1 (128990) resulting from a direct, destabilizing interaction with PAX3/FOXO1. Neither PAX3 nor FOXO1 shared the ability to regulate p57(Kip2) transcription.
The translocation t(2;13)(q35;q14) is frequently found in alveolar rhabdomyosarcoma (268220). Barr et al. (1993) determined that PAX3 (606597) was affected by this t(2;13) in alveolar rhabdomyosarcoma. Galili et al. (1993) identified FKHR as the chromosome 13 gene fused with PAX3 in t(2;13)(q35;q14). The translocation breakpoints occurred within an intron downstream of the paired box- and homeodomain-encoding regions of PAX3 and within an intron in the forkhead domain-encoding region of FKHR. RT-PCR detected the 5-prime-PAX3/3-prime-FKHR transcript from the der13 chromosome in all 7 t(2;13)-containing rhabdomyosarcoma cell lines examined. The shorter reciprocal transcript from the der2 chromosome was detected in 6 of the 7 t(2;13)-containing cell lines. The 837-amino acid PAX3/FKHR chimeric protein contains the intact PAX3 DNA-binding domain, the C-terminal half of the FKHR forkhead domain, and the C-terminal FKHR region. It had an apparent molecular mass of 97 kD by SDS-PAGE.
In a review of 28 published cases of alveolar rhabdomyosarcoma with cytogenetic studies, Whang-Peng et al. (1992) found the characteristic t(2;13) translocation in 64%; in 18% of cases they found a variant t(1;13)(p36;q14) translocation that was subsequently shown to result in fusion of the FKHR gene with the PAX7 gene (167410) on chromosome 1.
Davis and Barr (1997) demonstrated that in both the t(2;13) and the variant t(1;13) translocations, which generate PAX3/FKHR and PAX7/FKHR fusion proteins, respectively, there is overexpression of the fusion product in addition to functional alterations. In the t(2;13) translocation, transcription of PAX3/FKHR is increased relative to wildtype PAX3 by a copy number-independent process. In contrast, PAX7/FKHR overexpression results from fusion gene amplification.
FOXO3A (602681) has been linked to human longevity in Japanese, German, and Italian populations. Li et al. (2009) tested the genetic contribution of FOXO1A and FOXO3A to longevity in the Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were genotyped in 1,817 centenarians and younger individuals. Two SNPs of FOXO1A were associated with longevity in women (P = 0.01-0.005), whereas all 3 SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). One SNP from FOXO1A was not associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 and 1.38 (P = 0.0033 and 0.0063, respectively). The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (P = 0.0014); CGT: OR (95% CI) = 1.48 (P = 0.0035)] and in women [GTC: OR (95% CI) = 0.75 (P = 0.0094); CGT: OR (95% CI) = 1.47 (P = 0.0009)]. The association of FOXO1A with female longevity was replicated in 350 centenarians and 350 younger individuals from a different geographic location. The authors concluded that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by gender.
Anderson et al. (2001) produced transgenic mice in which Pax3-Fkhr expression was driven by mouse Pax3 promoter/enhancer sequences. Five independent lines expressed Pax3-Fkhr in the dorsal neural tube and lateral dermomyotome. Each line exhibited phenotypes that correlated with Pax3-Fkhr expression levels and predominantly involved pigmentary disturbances of the abdomen, hind paws, and tail, with additional neurologic-related alterations. Phenotypic severity could be increased by reducing Pax3 levels through matings with Pax3-defective Splotch mice, and interference between Pax3 and Pax3-Fkhr was apparent in transcription reporter assays. These data suggested that the tumor-associated PAX3-FKHR fusion protein interferes with normal PAX3 developmental functions as a prelude to transformation.
Nakae et al. (2002) investigated the mechanism of beta-cell failure in type 2 diabetes (125852). In mice, they identified Foxo1 as a component of insulin signaling in liver, adipose tissue, and beta-cells. Through a genetic analysis with gain- and loss-of-function alleles, they showed that the protein Foxo1 controls 2 important processes in the pathogenesis of type 2 diabetes: hepatic glucose production and beta-cell compensation of insulin resistance. Haploinsufficiency of the Foxo1 gene restored insulin sensitivity and rescued the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenic genes and increasing adipocyte expression of insulin-sensitizing genes. Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells resulted in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased expression of insulin promoter factor-1 (IPF1; 600733), also known as Pdx1. The data indicated that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes, and pancreatic beta-cells. Impaired insulin signaling to Foxo1 provides a unifying mechanism for the common metabolic abnormalities of type 2 diabetes.
Lagutina et al. (2002) generated mice carrying a Pax3-Fkhr knockin allele. Despite low expression of this allele, heterozygous offspring of Pax3-Fkhr chimeric mice showed developmental abnormalities, including intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. Heterozygotes also displayed malformations of some, but not all, hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. Lagutina et al. (2002) concluded that the Pax2-Fkhr allele causes lethal developmental defects in knockin mice but is insufficient to cause muscle tumors.
Relaix et al. (2003) found that mice expressing Fkhr/Pax3 displayed developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events resulted from overexpression of Met (164860), leading to constitutive activation of Met signaling. The gain-of-function phenotype was also characterized by overactivation of MyoD.
The C. elegans transcription factor hsf1 (140580) regulates the heat-shock response and influences aging. Reducing hsf1 activity accelerates tissue aging and shortens life span; Hsu et al. (2003) showed that hsf1 overexpression extends life span. Hsu et al. (2003) found that hsf1, like the transcription factor daf16, whose human homologs include FOXO1, FOXO3A (602681), and FOXO4 (MLLT7; 300033), is required for daf2-insulin/Igf1 receptor (147370) mutations to extend life span. Hsu et al. (2003) concluded that this is because hsf1 and daf16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
Kamei et al. (2004) found that transgenic mice with specific overexpression of human FOXO1A in skeletal muscle were smaller with a decreased lean muscle mass and exhibited impaired spontaneous activity on the running wheel test compared to controls. The skeletal muscle of the transgenic mice was pale and showed both atrophy and loss of type I fibers without morphologic abnormalities. Microarray, Northern blot, and Western blot analysis showed a decreased expression of many genes related to structural proteins of type I muscle fibers. Metabolically, the transgenic mice had impaired glucose tolerance and insulin resistance. Kamei et al. (2004) concluded that FOXO1A is involved in the negative regulation of skeletal muscle mass and that upregulation of the protein may lead to impaired muscle function.
Paik et al. (2007) generated null and conditional alleles for Foxo1, Foxo3, and Foxo4 to assess their role in cancer in vivo. Mice with germline or somatic deletion of up to 5 Foxo alleles, including Foxo1 +/- Foxo3 -/- Foxo4 -/- mice, had only modest neoplastic phenotypes. In contrast, broad somatic deletion of Foxo1, Foxo3, and Foxo4 engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas. Transcriptome and promoter analyses of differentially affected endothelium identified direct Foxo targets and revealed that Foxo regulation of these targets in vivo was highly context specific, even in the same cell type. Functional studies validated Spry2 (602466) and Pbx1 (176310), among others, as Foxo-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
Tothova et al. (2007) conditionally deleted Foxo1, Foxo3, and Foxo4 in the adult mouse hematopoietic system. Foxo-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative/Sca1-positive/Kit (164920)-positive compartment containing short- and long-term hematopoietic stem cell (HSC) populations. Foxo-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSCs. There was a marked context-dependent increase in reactive oxygen species (ROS) in Foxo-deficient HSCs compared with wildtype HSCs that correlated with changes in genes encoding regulators of ROS. In vivo treatment with an antioxidative agent resulted in reversion of the Foxo-deficient phenotype. Tothova et al. (2007) concluded that FOXO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment.
Biddinger et al. (2008) generated liver-specific Insr (147670)-knockout (LIRKO) mice and observed a marked predisposition to cholesterol gallstone formation that was due in part to disinhibition of Foxo1, which increased expression of the biliary cholesterol transporters Abcg5 (605459) and Abcg8 (605460) and resulted in an increase in biliary cholesterol secretion.
Plum et al. (2009) generated mice with POMC (176830)-neuron-specific ablation of Foxo1 and observed an increase in Cpe (114855) expression that resulted in selective increase of alpha-Msh and beta-endorphin, which are the products of CPE-dependent processing of POMC. This neuropeptide profile was associated with decreased food intake and normal energy expenditure in the POMC-Foxo1 -/- mice. CPE expression was downregulated by diet-induced obesity, and Foxo1 deletion offset that decrease, protecting against weight gain. Leptin (164160) curtailed food intake more markedly in POMC-Foxo1 -/- mice than in wildtype mice, consistent with increased sensitivity to leptin; unexpectedly, there was also a near doubling of leptin levels in the POMC-Foxo1 -/- mice. Moderate Cpe overexpression in the arcuate nucleus phenocopied features seen in the POMC-Foxo1 -/- mice. Plum et al. (2009) concluded that Foxo1 ablation in hypothalamic POMC neurons reduces food intake without concurrently decreasing energy expenditure or leptin levels, and that this effect is mediated by Cpe; they stated that this was the first time that hypophagia and reduced body weight had been uncoupled from energy expenditure and leptin levels.
Ouyang et al. (2009) generated mice with T cell-specific deletion of Foxo1 and found that these mice could overcome embryonic lethality associated with germline deletion. Flow cytometric analysis detected no changes in thymic T-cell development. However, peripheral T cells lacking Foxo1 exhibited an activated phenotype, effector cell differentiation, and autoantibody induction, with reduced numbers of naive T cells. Gene expression profiling identified Il7r (146661) as a target of Foxo1. Cell surface expression of Il7r was reduced in Foxo1 -/- T cells, and cell survival was not enhanced by Il7 (146660) treatment. Bone marrow chimera experiments revealed that diminished Il7r expression was a consequence of Foxo1 deficiency. Ouyang et al. (2009) concluded that FOXO1 has a critical role in T-cell tolerance and in naive T-cell homeostasis through induction of IL7R expression.
Ren et al. (2012) found that ablation of Foxo1 specifically in Agrp-positive hypothalamic neurons resulted in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to leptin and insulin in mice. Quantitative PCR and microarray analysis showed that Gpr17 (603071) was highly expressed in Agrp-positive mouse neurons and that Gpr17 expression increased during fasting. Gpr17 expression was decreased in Foxo1-deficient Agrp-positive neurons. Chromatin immunoprecipitation analysis confirmed that Foxo1 bound the Gpr17 promoter. Ren et al. (2012) concluded that downregulation of Gpr17, at least in part, mediates the anorexigenic phenotype of Foxo1-deficient Agrp-positive neurons.
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