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FLASH GENE
Symbol FOXO1 contributors: mct - updated : 17-08-2020
HGNC name forkhead box O1
HGNC id 3819
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a forkhead (FH, winged helix) domain
  • a conserved putative CDC2 phosphorylation site within the forkhead domain
  • two loops-wings- on the C-terminal side of helix-turn-helix homeo domain
  • a NLS (nuclear localization signal) in the C-terminal basic region of the DBD (DNA-binding domain)
  • a leucine-rich, leptomycin-B sensitive NES (nuclear export signal) located further downstream
    • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to rattus Foxo1a (92.91 pc)
    homolog to murine Foxo1 (93.53 pc)
    Homologene
    FAMILY
  • forkhead family of transcriptional activators
    • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,chromatin/chromosome
    text
  • nuclear/cytoplasmic shuttling
  • subcellular localization of FOXO1 is dependent on its post-translational modifications, particularly its phosphorylation status
  • co-localizes with ATF4 in the osteoblast nucleus
    • basic FUNCTION
  • embryonic transcriptional regulator, negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta cells, acting downstream of the insulin signaling pathway
  • having a tumor suppressor function by inhibiting cell proliferation and survival
  • playing critical roles in regulation of proliferation, apoptosis and control of oxidative stress
  • playing an important role in the regulation of energy metabolism, at least in part, through the up-regulation of PDK4 gene expression in skeletal muscle during starvation
  • representing a shared component of pathways integrating food intake and peripheral metabolism
  • expressed, regulated, and functionally active in cardiomyocytes and thus may contribute to apoptotic responses in heart
  • represses expression of musclin, a skeletal muscle-derived secretory factor
  • required for normal eye function
  • playing a role in apoptosis of neurons deprived of activity
  • acting as an activator to enhance ADIPOR promoter activity in the absence of insulin
  • nNuclear deacetylated FOXO1 promotes the transcription of genes involved in DNA repair and stress resistance, whereas acetylated FOXO1 promotes the expression of genes involved in apoptosis
  • negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components
  • considered to play a major role in the terminal
    • degradation of proteins delivered to lysosomes by endocytosis or autophagy
  • functions as a key integrator for the regulation of glucose and bile acid metabolism
  • responsible for glucose-induced induction of TXNIP
  • integrates insulin signaling with mitochondrial function
  • plays a crucial role in regulation of beta-cell function and metabolic effects of insulin in the liver
  • play an important role in a variety of processes, such as cell cycle arrest, cell death, tumor suppression, metabolism, and protection from oxidative stress
  • mediator of autophagy, having the ability to induce cell cycle arrest, DNA repair and apoptosis
  • early molecular regulator in the differentiation of mesenchymal cells into osteoblast
  • induces osteoblast differentiation through regulation and interaction with RUNX2 and is an early and important regulator of mesenchymal cell differentiation into osteoblasts
  • promotes inflammation by enhancing TLR4-mediated signalling in mature macrophages
  • regulates TLR4 inflammatory pathway signalling in macrophages
  • primary roles for FOXO1 and SIRT1 in regulating the cellular responses of pancreatic beta-cells to nitric oxide
  • required for nitric oxide-induced GADD45A expression
  • activated SIRT1 deacetylates FOXO1, thereby directing a transcriptional program that attenuates apoptosis and stimulates the expression of factors that protect pancreatic beta-cells from nitric oxide
  • essential for the maintenance of embryonic stem cells pluripotency
  • essential for allantois and cardiovascular morphogenesis
  • ATF4, FOXO1 synergize to regulate glucose metabolism, insulin production, and insulin sensitivity
  • is required specifically in endothelial cells to regulate formation of the heart and vasculature during development
  • FOXO1 regulates energy homeostasis by modulating gene expression in the hypothalamus
  • plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons
  • the effects of IL1B and insulin on FOXO1 are additive, albeit independent, with respect to the distribution of FOXO1 between the nucleus and cytosol
  • EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage
  • crucial for sustaining cardiomyocyte metabolism and cell survival
  • critical, direct regulator of Rag (recombination activating gene) transcription during B cell development
  • novel function in coordinating the response of keratinocytes to wounding through up-regulation of TGFB1 and other factors needed for keratinocyte migration and protection against oxidative stress
  • both NR3C1 and FOXO1 are required for ANGPTL4 transcription activation, and FOXO1 negatively mediates the suppressive effect of insulin
  • regulatory pathway by which the negative regulator FOXO1 and the positive regulator TBX21 play opposing roles in controlling NK cell development and effector functions
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    CDC2-FOXO1 signaling pathway
    a component
  • CDC2-FOXO1 signaling pathway may thus have diverse functions in cellular homeostasis, including regulation of neuronal death and degeneration in brain development and disease
  • component of the circuitry of embryonic stem cells pluripotency
  • unique FOXO1–VCAM1 axis that governs placental morphogenesis, a process that is essential for subsequent normal cardiovascular development and fetal life
    • INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • with PAX7 and MYCN (concomitant amplification)
  • insulin dependent regulator of PPARGC1
  • may play an important role in the regulation of lipolysis in adipocytes by controlling the expression of PNPLA2
  • NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain
  • upregulating MET in alveolar rhabdomyosarcoma with fusion protein PAX3-FOXO1A (reduction of CDKN1C levels by PAX3-FOXO1 is more likely to predispose cells to transformation by a secondary genetic event)
  • interacting with SKP2 for proteasomal degradation
  • target of FOXC1 (dysregulation of FOXO1 activities in the eye through FOXC1 loss of function mutations and gene duplications provides an explanation into how seemingly similar disorders can arise from both increases and decreases in FOXC1 gene dose)
  • links the phosphatidylinositol 3-kinase (PI 3-kinase) Akt cascade to gene expression that regulates cell growth, survival, and metabolism
  • interacting with IRS2 (reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling)
  • direct interaction between SIRT2 and FOXO1, enhancing insulin-stimulated phosphorylation of FOXO1, which in turn regulates FOXO1 nuclear and cytosolic localization
  • interacting with RFWD2 (RFWD2 functions as a FOXO1 ubiquitin E3 ligase to regulate FOXO1-mediated gene expression
  • PPP2R1A is a FOXO1 phosphatase (silencing of PPP2R1A protected FOXO1 from dephosphorylation and delayed FOXO1 nuclear translocation, confirming the physiologic role of PPP2R1A in the regulation of FOXO1 function
  • targeting of FOXO1 by MIR96 may contribute to transformation or maintenance of an oncogenic state in breast cancer cells
  • physical association of HOXA11 and FOXO1, and binding of both factors to an enhancer region of the decidual prolactin promoter
  • interacting with SIRT2 (a NAD+-dependent histone deacetylase), but this interaction was clearly decreased in response to serum starvation)
  • recruited and binds to the CTSL promoter
  • directly interacts with the promoter of RUNX2 and regulates its expression
  • suppression of FOXO1 function by EWSR1-FLI1 fusion protein may contribute to cellular transformation in Ewing's family tumors
  • binds to multiple enhancer-like elements within the TLR4 gene itself, as well as to sites in a number of TLR4 signalling pathway genes
  • CNKSR1 acts as a scaffold protein in several signaling pathways controlling the function of FOXO1 proteins
  • critical negative regulator of RUNX2 in prostate cancer cells
  • AKT1 is not the predominant regulator of FOXO1 in embryonic stem cells
  • essential upstream regulator of the VCAM1 gene
  • physically interacts with and promotes the transcriptional activity of ATF4 (FOXO1 and ATF4 cooperate to increase glucose levels and decrease glucose tolerance)
  • involvement of XBP1 in huntington pathogenesis probably due to an ER stress-independent mechanism involving the control of FOXO1 and autophagy levels
  • mediates the autocrine effect of endothelin-1 (EDN1) on endothelial cell survival
  • NR5A1 is a direct FOXO1 transcriptional target in the ventromedial hypothalamus
  • FOXO1 target GPR17 activates AGRP neurons to regulate food intake
  • FOXP3 bound gene loci with a decreased FOXO1 occupancy were significantly down-regulated in Treg cells in contrast to FOXP3 unbound genes or FOXP3 bound sites that have increased FOXO1
  • IL1B regulates FOXO1 activity through a novel SMPD3-dependent pathway
  • IL1B counteracts the AKT1-mediated insulin signals by increasing the overall cellular FOXO1 content and augmenting its nuclear localization
  • RIPOR2 is a new transcriptional target of FOXO1 that regulates RHOA activity
  • is a pivotal regulator of Treg cell function
  • negative regulator for virus-triggered IFN beta induction
  • interacted with IRF3 in a viral infection-dependent manner and promoted K48-linked polyubiquitination and degradation of IRF3 in the cytosol
  • up-regulate TXNIP expression in neurons and endothelial cells but to down-regulate TXNIP in liver
  • inhibits beta cell TXNIP transcription, suggesting that FOXO1 confers this inhibition by interfering with MLXIPL DNA binding at target gene promoters
  • MAPKAPK5 positively regulates Rag (recombination activating gene) transcription via phosphorylation of FOXO1 in developing B cells
  • E2F1/FOXO1/FOXO3 cooperation is a regulatory mechanism that places E2F1 apoptotic activity under the control of survival signaling
  • FOXO1 is upregulated by nutrient restriction (NR) in adipocytes and exerts the transcriptional control of lipid catabolism via the induction of lysosomal acid lipase (LIPA)
  • AKT1 is an inter-mediator between the upstream regulator, ALCAM, and downstream effector, FOXO1, in liver cancer cells
  • FOXO1 favors catecholamine synthesis because it is a potent regulator of the expression of DBH that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters
  • FOXO1 has important roles in promoting diabetic cardiomyopathy and controls MYH7 expression in the development of cardiac dysfunction
  • ZFAT is required for peripheral T-cell homeostasis through IL7R expression by controlling the FOXO1 protein
  • GAS6-FOXO1 signaling axis plays an important role in VCAM1 expression in the context of venous thromboembolism (VTE)
  • mechanistically, LAMTOR5 inhibited the expression of PCK1 through down-regulating transcription factor FOXO1 in hepatoma cells
  • PKNOX1 may likely control hepatic insulin sensitivity by targeting FOXO1 nuclear stability
  • EPS8L3 might likely promote proliferation by hyperactivating the AKT1 signaling pathway and subsequently inhibiting the FOXO1A transcriptional activity
  • mitochondrial FOXO1 responds to starvation leaving mitochondrial compartment by ROS-mediated activation of the mitochondrial phosphatase PTPMT1
  • FOXO1 is unable to maintain expression of key differentiation markers in CYB5R3-deficient beta cells, suggesting that CYB5R3 is required for FOXO1-dependent lineage stability
  • TRIM47 inhibited FOXO1 expression by ubiquitination and degradation of FOXO1, thereby promoting glioma growth and progression
    • cell & other
    REGULATION
    activated by FOXO3 and possibly by other FOXO factors in a positive feedback loop, which is disrupted by growth factors
    repressed by ANGPT1, via AKT activation, a potent inhibitor of the forkhead transcription factor FOXO1
    Phosphorylated by NLK
    Other regulated by phosphorylation and 14-3-3 proteins binding
    regulated by shear stress
    phosphorylated by CDC2 at Ser249 (disrupts FOXO1 interaction with 14-3-3 proteins)
    its activity is tightly regulated by the phosphoinositide-3-kinase-AKT (PI3K-Akt) pathway, which leads to phosphorylation, cytoplasmic retention and inactivation of FOXO1
    ASSOCIATED DISORDERS
    corresponding disease(s) ARMS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion     protein chimeric
    fused to PAX3 in alveolar rhabdomyosarcoma with translocation t(2;13)(q35;q14) and to PAX7 with translocation t(1;13)(p36;q14) (see BARMS1, BARMS2, BARMS13)
    constitutional     --over  
    early in the decidualization process
    constitutional       loss of function
    can improve hepatic metabolism during insulin resistance and the metabolic syndrome
    constitutional        
    silencing FOXO1 decreases the expression of RUNX2 and impairs bone formation
    tumoral        
    enhanced prostate cancer cell migration in a RUNX2-dependent manner
    Susceptibility
  • to type 2 diabetes (minor contributor)
  • to keratoconus
    • Variant & Polymorphism SNP
  • haplotype 3 'TCA' have higher HbA1c levels and a 1.14-fold higher all-cause mortality risk, attributable to death from diabetes, for which a 2.43-fold increase was observed
  • SNP rs2721068 was significantly associated with type 2 diabetes
  • rs2721051 near FOXO1 strongly associated to keratoconus
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancermuscle 
    partial inhibition of hepatic Foxo1 might be a good target to prevent the progression of a vicious cycle that causes metabolic disease
    ANIMAL & CELL MODELS
  • FoxO1-deficient embryos manifest progressive apoptotic cell death
  • mice lacking FOXO1 in steroidogenic factor 1 (NR5A1) neurons of the ventromedial hypothalamus are lean due to increased energy expenditure
  • mice with Treg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of Treg cells