FOXO1 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the FOXO1 gene, its protein product, associated diseases, and expression patterns.
Gene Information Card
| Symbol | FOXO1 |
|---|---|
| Full Name | forkhead box O1 |
| Gene Type | protein coding |
| Chromosomal Location | 13q14.11 |
| NCBI Gene ID | 2308 ncbi.nlm.nih.gov/gene/2308 |
| Ensembl ID | ENSG00000150907 |
| UniProt ID | Q12778 |
| OMIM ID | 136533 |
| HGNC ID | 3819 |
| Aliases | FKHR, FOXO1A, forkhead in rhabdomyosarcoma |
Description
FOXO1 (forkhead box O1) is a transcription factor belonging to the forkhead box O family. It regulates genes involved in cell cycle, apoptosis, glucose metabolism, oxidative stress response, and DNA repair. FOXO1 activity is modulated by post-translational modifications (phosphorylation, acetylation, ubiquitination) in response to growth factors and stress signals. It plays a critical role in insulin signaling and tumor suppression, and its dysregulation is implicated in various cancers and metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Rhabdomyosarcoma | Chromosomal translocations (e.g., t(2;13)(q35;q14) or t(1;13)(p36;q14)) fuse FOXO1 with PAX3 or PAX7, creating oncogenic fusion proteins that disrupt myogenic differentiation and promote tumorigenesis. | COSMIC, ClinVar, PMID: 28346458 |
| Acute lymphoblastic leukemia (ALL) | FOXO1 rearrangements (e.g., t(1;13)(p36;q14) with PAX7) are rare but associated with poor prognosis; fusion proteins alter transcriptional programs. | COSMIC, PMID: 28637621 |
| Alveolar rhabdomyosarcoma | FOXO1 gene fusions (PAX3-FOXO1 or PAX7-FOXO1) are pathognomonic and drive aggressive tumor behavior. | COSMIC, PMID: 28346458 |
| Type 2 diabetes | FOXO1 regulates hepatic gluconeogenesis; increased FOXO1 activity contributes to insulin resistance and hyperglycemia. | OMIM, PMID: 15692564 |
| Prostate cancer | FOXO1 loss or cytoplasmic sequestration leads to increased cell proliferation and survival; reduced nuclear FOXO1 correlates with poor prognosis. | PMID: 20534588 |
| Breast cancer | FOXO1 acts as a tumor suppressor; loss of expression or activity promotes epithelial-mesenchymal transition and metastasis. | PMID: 22108914 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adipose tissue | 12.4 | Medium |
| Skeletal muscle | 10.8 | Medium |
| Liver | 8.2 | Low |
| Heart | 7.5 | Low |
| Brain | 5.1 | Low |
| Kidney | 4.3 | Low |
| Lung | 3.2 | Low |
| Spleen | 2.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.2 | Cervical adenocarcinoma; moderate expression |
| K-562 | 8.4 | Chronic myelogenous leukemia; low expression |
| MCF7 | 12.1 | Breast adenocarcinoma; moderate expression |
| A549 | 6.3 | Lung carcinoma; low expression |
| HepG2 | 9.8 | Hepatocellular carcinoma; moderate expression |
| T-47D | 11.5 | Breast ductal carcinoma; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| PAX3-FOXO1 fusion | Chromosomal translocation t(2;13)(q35;q14) | ~55% of alveolar rhabdomyosarcoma | Oncogenic fusion protein with aberrant transcriptional activity |
| PAX7-FOXO1 fusion | Chromosomal translocation t(1;13)(p36;q14) | ~20% of alveolar rhabdomyosarcoma | Oncogenic fusion protein; associated with younger age and better prognosis than PAX3-FOXO1 |
| Missense mutations (e.g., p.Ser219Ala) | Single nucleotide substitution | Rare in cancers; frequency <1% | May affect phosphorylation and nuclear localization |
| Deletions | Loss of chromosomal region 13q14 | Observed in some leukemias and lymphomas | Loss of tumor suppressor function |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., deletions, inactivating missense) reduce FOXO1 transcriptional activity, leading to unchecked cell proliferation and survival, contributing to tumorigenesis.
Gain of Function (GOF)
Gain-of-function is primarily seen in fusion proteins (PAX3/7-FOXO1) that acquire novel DNA-binding and transactivation domains, driving oncogenic gene expression programs.
Dominant Negative (DN)
Some FOXO1 mutants may act in a dominant-negative manner by competing with wild-type FOXO1 for DNA binding or cofactor interaction, thereby suppressing normal FOXO1 target gene expression.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • protein binding | • transcription coregulator binding |
| • nucleus | • cytoplasm |
| • regulation of transcription by RNA polymerase II | • apoptotic process |
| • cell cycle arrest | • glucose homeostasis |
| • response to oxidative stress | • insulin receptor signaling pathway |
Pathways
• PI3K-Akt signaling pathway
• FoxO signaling pathway
• Insulin signaling pathway
• AMPK signaling pathway
• Cell cycle regulation
• Apoptosis signaling
Protein Summary
The FOXO1 protein (UniProt Q12778) is a 655-amino acid transcription factor with a conserved forkhead DNA-binding domain. It shuttles between nucleus and cytoplasm; phosphorylation by AKT at Thr24, Ser256, and Ser319 promotes cytoplasmic retention and inactivation. In the nucleus, FOXO1 binds to insulin response sequences (IRS) and regulates target genes such as p27, p21, Bim, and G6PC. Post-translational modifications (acetylation, ubiquitination) modulate its stability and activity. FOXO1 is critical for metabolic homeostasis and tumor suppression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FOXO1 Knockout HEK293 Cell Line | EDJ-KQ50280 | Human | 2308 | Details Get a Quote |
| FOXO1 Knockout HeLa Cell Line | EDJ-KQ53247 | Human | 2308 | Details Get a Quote |
| FOXO1 Knockout A-549 Cell Line | EDJ-KQ61729 | Human | 2308 | Details Get a Quote |
| FOXO1 Knockout HCT 116 Cell Line | EDJ-KQ70215 | Human | 2308 | Details Get a Quote |
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