FOXO1 (Forkhead box O1)

2008-05-01   Roddy OConnor , Frederic G Barr 

Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA





The FOXO1 gene extends approximately 110 kb and consists of 3 exons.


Only a single transcript has been reported to be expressed from the FOXO1 gene, measuring 5.7 kb in length and containing an open reading frame of 1965 bp. At the RNA level, the gene is widely expressed.



A single protein of 655 amino acids is expressed. This protein is a transcription factor with a forkhead box-containing DNA binding domain in the N-terminal region and an acidic, serine/threonine-rich transcriptional activation domain in the C-terminal region.


The protein is widely expressed. Covalent attachment of ubiquitin moieties (polyubiquitination) targets FOXO1 protein for degradation, and thus FOXO1 expression can be regulated by the ubiquitin-dependent proteasome. AKT is implicated in the regulation of FOXO1 expression by its enhancement of FOXO1 ubiquitination and proteolysis.


The FOXO1 protein shuttles between the nucleus and cytoplasm. The subcellular localization and hence the transcriptional activity of FOXO1 is regulated by intracellular kinases. FOXO1 contains three AKT-phosphorylation motifs [RxRxx(S/T)]. Phosphorylation of these sites by AKT promotes nuclear exclusion, association with 14-3-3 adaptor proteins and cytosolic retention. The serum and glucocorticoid-inducible kinase ( SGK ), dual-specificity tyrosine-phosphorylated regulated kinase DYRK1A and cyclin-dependent kinase 2 ( CDK2 ) may also similarly phosphorylate FOXO1 and contribute to its subceullar localization, thereby acting combinatorially to suppress FOXO1 transcriptional activity. Although the role of phosphatases in FOXO1 activation is unclear, PTEN may have a role in countering the effects of these kinases.


FOXO1 plays an important role in many cellular processes. As a transcription factor, FOXO1 induces expression of target genes involved in apoptosis, glucose metabolism, cell cycle progression, and differentiation. There is increasing evidence of a role for FOXO1 as a tumor suppressor. FOXO1 transcriptional responses are also implicated in cellular protection following DNA damage and oxidative stress, which may be related to a role in longevity.


The first FOX transcription factor fork head was identified in Drosophila. The subsequent cloning of mammalian FOX transcription factors revealed a common DNA-binding domain (forkhead box) that is highly conserved across species including Drosophila melanogaster, C. elegans and Homo sapiens. Within the larger FOX transcription factor family, there is a subfamily of which FOXO1 is the prototype. Additional members of this FOXO subfamily are: FOXO3 (FKHRL1, FOXO2), FOXO4 (AFX), FOXO6.
A gene homologous to FOXO subfamily members, daf-16, has also been identified in C. elegans and has facilitated analysis of the functional regulation of mammalian FOXO subfamily members. FOXO members share consensus phosphorylaton motifs for multiple kinases including AKT, CDK2, DYRK1A and SGK. Phosphorylation of these motifs regulates subcellular localization, DNA affinity, and protein-protein interactions. Of note, three of the genes in the FOXO1 subfamily are involved in cancer associated-chromosomal translocations. In addition to the rearrangement of FOXO1 in alveolar rhabdomyosarcoma (discussed below), FOXO3 and FOXO4 are joined with the MLL gene by translocations in acute myeloid leukemias.


Atlas Image
Figure 1. Diagram of t(2;13)(q35;q14) and t(1;13)(p36;q14) chromosomal translocations.


Inherited mutations of FOXO1 have not been identified.


The FOXO1 gene is rearranged by the recurrent acquired chromosomal translocations - t(2;13)(q35;q14) and t(1;13)(p36;q14) - in the myogenic soft tissue cancer alveolar rhabdomyosarcoma. As a result of the 2;13 or 1;13 translocation, portions of the PAX3 or PAX7 gene (on chromosomes 2 or 1, respectively) are juxtaposed with portions of the FOXO1 gene. In particular, the 5 region of PAX3 or PAX7, including the first seven exons of either gene, is joined to the 3 region of FOXO1, including its last two exons. Though the reciprocal chimeric gene is also generated, the PAX3-FOXO1 and PAX7-FOXO1 chimeric genes are more consistent and highly expressed, and result in expression of fusion proteins consisting of the intact PAX3 or PAX7 N-terminal DNA binding domain fused in-framed to the intact FOXO1 C-terminal transcriptional activation domain.
FOXO1 was identified as only gene within a minimal common region of deletion in chromosomal region 13q14 in prostate carcinoma. FOXO1 deletion was detected in about 30% of prostate cancer samples, and additional cases were identified with reduced expression without evidence of deletion. Based on functional testing in prostate cancer cell lines that indicated that FOXO1 affected cell proliferation, survival, and androgen receptor signaling, the combined data indicates that FOXO1 is a tumor suppressor gene in prostate cancer.

Implicated in

Entity name
Alveolar Rhabdomyosarcoma (ARMS)
ARMS is one subtype of a family of pediatric soft tissue tumors that is related to the skeletal muscle lineage. In contrast to embryonal rhabdomyosarcoma (ERMS), the other major subtype in this family, ARMS often occurs in adolescents and young adults, with primary tumors located in the vicinity of skeletal muscle, such as in the extremities and trunk.
The overall prognosis for patients with ARMS is less favorable compared to those with ERMS. The three year survival rate for patients without metastatic diseae was 66% (IRS-IV clinical trial), and evidence of metastasis decreased the survival rate to only 16%. The pathogenesis of metastatic ARMS is associated with an early and wide dissemination, often involving bone marrow, and to poor response to chemotherapy. One study also indicates that for metastatic patients, tumors with a PAX3-FKHR fusion have a poorer outcome than tumors with a PAX7-FKHR fusion. In contrast, there is no reported difference in outcome between these subtypes in patients with non-metastatic tumors.
Translocations involving the q14 band on chromosome 13 and the q35 band on chromosome 2 - t(2;13)(q35;q14) - distinguish ARMS from other soft tissue sarcomas. An additional 1;13 translocation - t(1;13)(p36;q14) - has been identified in a smaller number of ARMS cases.
Atlas Image
Figure 2. Generation of chimeric genes by the 2;13 and 1;13 translocations in ARMS. The exons of the wild-type and fusion genes are shown as boxes above each map and the translocation breakpoint distributions are shown as line segments below the map of the wild-type genes
Atlas Image
Figure 3. Comparison of wild-type and fusion products associated with the 2;13 and 1;13 translocations. The paired box, octapeptide, homeobox and fork head domain are indicated as open boxes, and transcriptional domains (DNA binding domain, DBD; transcriptional activiation domain) are shown as solid bars. The sites phosphorylated by Akt are indicated by stars. The vertical dash line indicates the translocation fusion point
Entity name
Prostate carcinoma
Adenocarcinoma of the prostate is a malignant tumor arising from the glandular epithelium of the prostate gland.
In several studies in prostate cancer correlating outcome and chromosomal changes detected by allelic loss or comparative genomic hybridization, deletions or losses involving chromosomal region 13q14 were not found to be correlated with significant differences in outcome.
One of the most frequent deletions in prostate cancer involves the q arm of chromosome 13. There are two common regions of deletion in the q arm of chromosome 13: 13q14 and 13q21.


Atlas Image


Pubmed IDLast YearTitleAuthors
153429122004Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins.Aoki M et al
80989851993Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma.Barr FG et al
86435961996Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma.Bennicelli JL et al
103774301999Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1.Biggs WH 3rd et al
126065792003FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts.Bois PR et al
101022731999Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Brunet A et al
116897112001Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451.De Ruiter ND et al
159054042005Functional interaction between beta-catenin and FOXO in oxidative stress signaling.Essers MA et al
151843862004Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice.Furuyama T et al
129131102003FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.Gilley J et al
170386212006CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage.Huang H et al
128917092003Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal muscle satellite cells.Machida S et al
149802222004Mammalian SIRT1 represses forkhead transcription factors.Motta MC et al
125309682003The forkhead transcription factor Foxo1 regulates adipocyte differentiation.Nakae J et al
110739962000Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN.Nakamura N et al
158906772005The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription.Perrot V et al
125177442003Akt activation promotes degradation of tuberin and FOXO3a via the proteasome.Plas DR et al
161005712005Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.Potente M et al
127545252003Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Puigserver P et al
150842592004Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.Seoane J et al
120399292002PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group.Sorensen PH et al
119944542002The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2.Stahl M et al
150056552004The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.Van Der Heide LP et al
25663861989The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo.Weigel D et al
161136432005The ubiquitin signal: assembly, recognition and termination. Symposium on ubiquitin and signaling.Wilkinson KD et al
113111202001The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site.Woods YL et al
152867102004Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoprotein.Xia SJ et al
106024881999Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt.del Peso L et al
169642482006FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.van der Horst A et al

Other Information

Locus ID:

NCBI: 2308
MIM: 136533
HGNC: 3819
Ensembl: ENSG00000150907


dbSNP: 2308
ClinVar: 2308
TCGA: ENSG00000150907


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Insulin signaling pathwayKEGGko04910
Prostate cancerKEGGko05215
Insulin signaling pathwayKEGGhsa04910
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
PI3K-Akt signalingKEGGhsa_M00676
PI3K-Akt signalingKEGGM00676
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the nucleusREACTOMER-HSA-198693
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Developmental BiologyREACTOMER-HSA-1266738
Regulation of beta-cell developmentREACTOMER-HSA-186712
Regulation of gene expression in beta cellsREACTOMER-HSA-210745
AKT-mediated inactivation of FOXO1AREACTOMER-HSA-211163
Insulin resistanceKEGGhsa04931
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA443560Breast NeoplasmsDiseaseClinicalAnnotation, VariantAnnotationassociatedPD
PA445113NeutropeniaDiseaseClinicalAnnotation, VariantAnnotationassociatedPD
PA445204Ovarian NeoplasmsDiseaseMultilinkAnnotationassociated26554863
PA449165cyclophosphamideChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA449476epirubicinChemicalClinicalAnnotation, VariantAnnotationassociatedPD


Pubmed IDYearTitleCitations
151094992004Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.845
214400112011Akt, FoxO and regulation of apoptosis.263
195742232009Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells.230
217081912011FoxO transcription factors; Regulation by AKT and 14-3-3 proteins.221
161005712005Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.193
205438402010Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.193
164926652006FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.170
160769592005Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation.158
189510902008Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.150
120399292002PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group.149


Roddy OConnor ; Frederic G Barr

FOXO1 (Forkhead box O1)

Atlas Genet Cytogenet Oncol Haematol. 2008-05-01

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