Human Gene FOXO1 (uc001uxl.4)
  Description: Homo sapiens forkhead box O1 (FOXO1), mRNA.
RefSeq Summary (NM_002015): This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008].
Transcript (Including UTRs)
   Position: hg19 chr13:41,129,801-41,240,734 Size: 110,934 Total Exon Count: 3 Strand: -
Coding Region
   Position: hg19 chr13:41,133,660-41,240,349 Size: 106,690 Coding Exon Count: 2 

Page IndexSequence and LinksUniProtKB CommentsPrimersGenetic AssociationsMalaCards
CTDGene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein Structure
Other SpeciesGO AnnotationsmRNA DescriptionsPathwaysOther NamesModel Information
Methods
Data last updated at UCSC: 2013-06-14

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr13:41,129,801-41,240,734)mRNA (may differ from genome)Protein (655 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
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UniProtKBWikipediaBioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
  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";

-  Primer design for this transcript
 

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Click here to load the transcript sequence and exon structure into Primer3Plus

Exonprimer can design one pair of Sanger sequencing primers around every exon, located in non-genic sequence.
Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3


-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): FOXO1
CDC HuGE Published Literature: FOXO1

-  MalaCards Disease Associations
  MalaCards Gene Search: FOXO1
Diseases sorted by gene-association score: rhabdomyosarcoma 2, alveolar* (503), rhabdomyosarcoma (26), muscle cancer (10), muscle hypertrophy (4), skeletal muscle cancer (3), glucose intolerance (3), breast cancer (2), prostate cancer (2), ewing sarcoma (2), microphthalmia, isolated 1 (1), childhood kidney cell carcinoma (1), leigh syndrome (1), botryoid rhabdomyosarcoma (1), diabetes mellitus, noninsulin-dependent (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 45.18 RPKM in Ovary
Total median expression: 596.06 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -181.02385-0.470 Picture PostScript Text
3' UTR -873.743385-0.258 Picture PostScript Text

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.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR001766 - TF_fork_head
IPR018122 - TF_fork_head_CS
IPR011991 - WHTH_trsnscrt_rep_DNA-bd

Pfam Domains:
PF00250 - Forkhead domain
PF16675 - KIX-binding domain of forkhead box O, CR2
PF16676 - Transactivation domain of FOXO protein family

SCOP Domains:
46785 - "Winged helix" DNA-binding domain

Protein Data Bank (PDB) 3-D Structure
MuPIT help
3CO6 - X-ray MuPIT 3CO7 - X-ray MuPIT 3COA - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on Q12778
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The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  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.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologGenome BrowserGenome BrowserGenome BrowserGenome BrowserNo ortholog
Gene DetailsGene Details Gene DetailsGene Details 
Gene SorterGene Sorter Gene SorterGene Sorter 
 RGDEnsemblFlyBaseWormBase 
 Protein SequenceProtein SequenceProtein SequenceProtein Sequence 
 AlignmentAlignmentAlignmentAlignment 

-  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

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005739 mitochondrion
GO:0005829 cytosol


-  Descriptions from all associated GenBank mRNAs
  AK310511 - Homo sapiens cDNA, FLJ17553.
AF032885 - Homo sapiens forkhead protein (FKHR) mRNA, complete cds.
BX648278 - Homo sapiens mRNA; cDNA DKFZp686B20125 (from clone DKFZp686B20125).
LF213864 - JP 2014500723-A/21367: Polycomb-Associated Non-Coding RNAs.
U02310 - Human fork head domain protein (FKHR) mRNA, complete cds.
BC070065 - Homo sapiens forkhead box O1, mRNA (cDNA clone MGC:87303 IMAGE:30345006), complete cds.
BC021981 - Homo sapiens forkhead box O1, mRNA (cDNA clone MGC:1750 IMAGE:2959021), complete cds.
BT007455 - Homo sapiens forkhead box O1A (rhabdomyosarcoma) mRNA, complete cds.
MA449441 - JP 2018138019-A/21367: Polycomb-Associated Non-Coding RNAs.
U36922 - Human fork head domain protein (FKHR) mRNA, 3' end.
JD504811 - Sequence 485835 from Patent EP1572962.
JD134489 - Sequence 115513 from Patent EP1572962.
JD197000 - Sequence 178024 from Patent EP1572962.
JD079279 - Sequence 60303 from Patent EP1572962.
JD223088 - Sequence 204112 from Patent EP1572962.
JD348629 - Sequence 329653 from Patent EP1572962.
JD359186 - Sequence 340210 from Patent EP1572962.
JD464643 - Sequence 445667 from Patent EP1572962.
JD206641 - Sequence 187665 from Patent EP1572962.
JD539087 - Sequence 520111 from Patent EP1572962.
JD283993 - Sequence 265017 from Patent EP1572962.
JD531161 - Sequence 512185 from Patent EP1572962.
JD312684 - Sequence 293708 from Patent EP1572962.
JD296214 - Sequence 277238 from Patent EP1572962.
JD052642 - Sequence 33666 from Patent EP1572962.
JD304630 - Sequence 285654 from Patent EP1572962.
JD047198 - Sequence 28222 from Patent EP1572962.
JD074382 - Sequence 55406 from Patent EP1572962.
JD534295 - Sequence 515319 from Patent EP1572962.
JD160235 - Sequence 141259 from Patent EP1572962.
U02308 - Human PAX-3-FKHR gene fusion mRNA, partial cds.
JD101505 - Sequence 82529 from Patent EP1572962.
JD515733 - Sequence 496757 from Patent EP1572962.
JD360184 - Sequence 341208 from Patent EP1572962.
JD291912 - Sequence 272936 from Patent EP1572962.
JD526406 - Sequence 507430 from Patent EP1572962.
JD355049 - Sequence 336073 from Patent EP1572962.
JD566908 - Sequence 547932 from Patent EP1572962.
JD048964 - Sequence 29988 from Patent EP1572962.
U02368 - Human PAX3/forkhead transcription factor gene fusion mRNA, complete cds.
JD540075 - Sequence 521099 from Patent EP1572962.
JD499848 - Sequence 480872 from Patent EP1572962.
JD551418 - Sequence 532442 from Patent EP1572962.
JD280592 - Sequence 261616 from Patent EP1572962.
JD121202 - Sequence 102226 from Patent EP1572962.
AX229886 - Sequence 12 from Patent WO0162959.
BC008826 - Homo sapiens cDNA clone IMAGE:4099446, **** WARNING: chimeric clone ****.
JD223517 - Sequence 204541 from Patent EP1572962.
JD545118 - Sequence 526142 from Patent EP1572962.
JD072508 - Sequence 53532 from Patent EP1572962.
EU446645 - Synthetic construct Homo sapiens clone IMAGE:100070326; IMAGE:100011854; FLH258331.01L paired box 3 (PAX3) gene, encodes complete protein.
HQ824715 - Homo sapiens Pax7-forkhead fusion protein mRNA, partial cds.
LF206114 - JP 2014500723-A/13617: Polycomb-Associated Non-Coding RNAs.
JX141474 - Homo sapiens FKHR-PAX3 fusion protein isoform c mRNA, complete cds.
JX141475 - Homo sapiens FKHR-PAX3 fusion protein isoform d mRNA, complete cds.
JX141476 - Homo sapiens FKHR-PAX3 fusion protein isoform e mRNA, complete cds.
JD426312 - Sequence 407336 from Patent EP1572962.
JD081559 - Sequence 62583 from Patent EP1572962.
JD520337 - Sequence 501361 from Patent EP1572962.
JD520336 - Sequence 501360 from Patent EP1572962.
JD405717 - Sequence 386741 from Patent EP1572962.
JD396532 - Sequence 377556 from Patent EP1572962.
JD288921 - Sequence 269945 from Patent EP1572962.
LF351532 - JP 2014500723-A/159035: Polycomb-Associated Non-Coding RNAs.
JD158019 - Sequence 139043 from Patent EP1572962.
JD129611 - Sequence 110635 from Patent EP1572962.
JD187220 - Sequence 168244 from Patent EP1572962.
MA587109 - JP 2018138019-A/159035: Polycomb-Associated Non-Coding RNAs.
MA441691 - JP 2018138019-A/13617: Polycomb-Associated Non-Coding RNAs.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04910 - Insulin signaling pathway
hsa05200 - Pathways in cancer
hsa05215 - Prostate cancer

BioCarta from NCI Cancer Genome Anatomy Project
h_aktPathway - AKT Signaling Pathway

Reactome (by CSHL, EBI, and GO)

Protein Q12778 (Reactome details) participates in the following event(s):

R-HSA-211164 AKT phosphorylates FOXO1A
R-HSA-5692779 p-S182 MAPKAPK5 phosphorylates FOXO1
R-HSA-211178 Phosphorylated FOXO1A is excluded from the nucleus
R-HSA-5692785 p-S215 FOXO1 binds RAG gene
R-HSA-199299 AKT can phosphorylate forkhead box transcription factors
R-HSA-2399992 AKT1 E17K mutant phosphorylates forkhead box transcription factors
R-HSA-211163 AKT-mediated inactivation of FOXO1A
R-HSA-5687128 MAPK6/MAPK4 signaling
R-HSA-198693 AKT phosphorylates targets in the nucleus
R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-6785807 Interleukin-4 and 13 signaling
R-HSA-210745 Regulation of gene expression in beta cells
R-HSA-5683057 MAPK family signaling cascades
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-2219528 PI3K/AKT Signaling in Cancer
R-HSA-449147 Signaling by Interleukins
R-HSA-186712 Regulation of beta-cell development
R-HSA-162582 Signal Transduction
R-HSA-9006925 Intracellular signaling by second messengers
R-HSA-5663202 Diseases of signal transduction
R-HSA-1280215 Cytokine Signaling in Immune system
R-HSA-1266738 Developmental Biology
R-HSA-1643685 Disease
R-HSA-168256 Immune System

-  Other Names for This Gene
  Alternate Gene Symbols: FKHR, FOXO1A, FOXO1_HUMAN, NM_002015, NP_002006, O43523, Q12778, Q5VYC7, Q6NSK6
UCSC ID: uc001uxl.4
RefSeq Accession: NM_002015
Protein: Q12778 (aka FOXO1_HUMAN or FXO1_HUMAN)
CCDS: CCDS9371.1

-  Gene Model Information
 
category: coding nonsense-mediated-decay: no RNA accession: NM_002015.3
exon count: 3CDS single in 3' UTR: no RNA size: 5738
ORF size: 1968CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 4115.00frame shift in genome: no % Coverage: 100.00
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.