ID:FOXO1_HUMAN DESCRIPTION: RecName: Full=Forkhead box protein O1; AltName: Full=Forkhead box protein O1A; AltName: Full=Forkhead in rhabdomyosarcoma; FUNCTION: Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'- TT[G/A]TTTAC-3'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. SUBUNIT: Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import (By similarity). Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. INTERACTION: P06493:CDK1; NbExp=5; IntAct=EBI-1108782, EBI-444308; Q92793:CREBBP; NbExp=2; IntAct=EBI-1108782, EBI-81215; P03372:ESR1; NbExp=2; IntAct=EBI-1108782, EBI-78473; Q14192:FHL2; NbExp=8; IntAct=EBI-1108782, EBI-701903; Q96EB6:SIRT1; NbExp=3; IntAct=EBI-1108782, EBI-1802965; Q923E4:Sirt1 (xeno); NbExp=2; IntAct=EBI-1108782, EBI-1802585; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between the cytoplasm and nucleus. Largely nuclear in unstimulated cells. In osteoblasts, colocalizes with ATF4 and RUNX2 in the nucleus (By similarity). Insulin-induced phosphorylation at Ser-256 by PKB/AKT1 leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3 proteins and nuclear export to the cytoplasm where it is degraded by the ubiquitin-proteosomal pathway. Phosphorylation at Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes nuclear accumulation. Phosphorylation by NLK results in nuclear export. Translocates to the nucleus upon oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1. SGK1-mediated phosphorylation also results in nuclear translocation. Retained in the nucleus under stress stimuli including oxidative stress, nutrient deprivation or nitric oxide. Retained in the nucleus on methylation. TISSUE SPECIFICITY: Ubiquitous. INDUCTION: Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter. PTM: Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Phosphorylated upon DNA damage, probably by ATM or ATR. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta- cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PTM: Ubiquitinated by SRT2. Ubiquitination leads to proteasomal degradation. PTM: Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress (By similarity). PTM: Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser- 256. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation. DISEASE: Defects in FOXO1 are a cause of rhabdomyosarcoma type 2 (RMS2) [MIM:268220]. It is a form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchimal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note=Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator. SIMILARITY: Contains 1 fork-head DNA-binding domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FOXO1ID83ch13q14.html";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q12778
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0000989 transcription factor activity, transcription factor binding GO:0001078 transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0001223 transcription coactivator binding GO:0001227 transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0003677 DNA binding GO:0003682 chromatin binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0005515 protein binding GO:0008013 beta-catenin binding GO:0008134 transcription factor binding GO:0031625 ubiquitin protein ligase binding GO:0043565 sequence-specific DNA binding GO:0051721 protein phosphatase 2A binding
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0001568 blood vessel development GO:0001659 temperature homeostasis GO:0001678 cellular glucose homeostasis GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006357 regulation of transcription from RNA polymerase II promoter GO:0006473 protein acetylation GO:0006914 autophagy GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0008286 insulin receptor signaling pathway GO:0009267 cellular response to starvation GO:0009653 anatomical structure morphogenesis GO:0010508 positive regulation of autophagy GO:0019221 cytokine-mediated signaling pathway GO:0030154 cell differentiation GO:0031018 endocrine pancreas development GO:0032868 response to insulin GO:0032869 cellular response to insulin stimulus GO:0032873 negative regulation of stress-activated MAPK cascade GO:0034599 cellular response to oxidative stress GO:0035947 regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter GO:0042127 regulation of cell proliferation GO:0042593 glucose homeostasis GO:0043065 positive regulation of apoptotic process GO:0043066 negative regulation of apoptotic process GO:0045444 fat cell differentiation GO:0045599 negative regulation of fat cell differentiation GO:0045722 positive regulation of gluconeogenesis GO:0045732 positive regulation of protein catabolic process GO:0045892 negative regulation of transcription, DNA-templated GO:0045893 positive regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0070166 enamel mineralization GO:0070301 cellular response to hydrogen peroxide GO:0070417 cellular response to cold GO:0071455 cellular response to hyperoxia GO:0071549 cellular response to dexamethasone stimulus GO:0071732 cellular response to nitric oxide GO:0090090 negative regulation of canonical Wnt signaling pathway GO:0097009 energy homeostasis GO:0097150 neuronal stem cell population maintenance GO:1902617 response to fluoride GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress GO:2000177 regulation of neural precursor cell proliferation GO:2000377 regulation of reactive oxygen species metabolic process
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
