FOXO3 Gene: Forkhead Box O3 – Longevity, Cell Survival, and Disease
A comprehensive biomedical overview of FOXO3, a transcription factor implicated in aging, cancer, and metabolic disorders.
Gene Information Card
| Symbol | FOXO3 |
|---|---|
| Full Name | Forkhead box O3 |
| Gene Type | Protein coding |
| Chromosomal Location | 6q21 |
| NCBI Gene ID | 2309 ncbi.nlm.nih.gov/gene/2309 |
| Ensembl ID | ENSG00000118689 |
| UniProt ID | O43524 |
| OMIM ID | 602681 |
| HGNC ID | 3821 |
| Aliases | FOXO3A, AF6q21, FKHRL1, FOXO2 |
Description
FOXO3 (Forkhead box O3) is a transcription factor belonging to the forkhead box O family. It regulates genes involved in apoptosis, cell cycle arrest, DNA repair, oxidative stress resistance, and metabolism. FOXO3 is a key mediator of insulin/IGF-1 signaling and is implicated in longevity, cancer, and age-related diseases. Its activity is regulated by post-translational modifications including phosphorylation, acetylation, and ubiquitination, which control its nuclear-cytoplasmic shuttling and transcriptional activity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | FOXO3 acts as a tumor suppressor by inducing apoptosis and cell cycle arrest. Loss of function or cytoplasmic sequestration promotes tumorigenesis. | COSMIC, ClinVar, literature |
| Longevity/Healthy Aging | Genetic variants in FOXO3 are associated with human longevity, likely through enhanced stress resistance and metabolic regulation. | OMIM, GWAS studies |
| Type 2 Diabetes | FOXO3 regulates hepatic gluconeogenesis and insulin sensitivity; dysregulation contributes to insulin resistance. | Literature, ClinVar |
| Cardiovascular Disease | FOXO3 protects against cardiac hypertrophy and ischemia-reperfusion injury via antioxidant and anti-apoptotic effects. | Literature, OMIM |
| Neurodegenerative Disorders | FOXO3 promotes neuronal survival under oxidative stress; altered activity is linked to Alzheimer's and Parkinson's disease. | Literature, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal Muscle | 10.2 | Medium |
| Heart | 8.5 | Medium |
| Brain | 7.8 | Medium |
| Liver | 6.1 | Low |
| Kidney | 5.9 | Low |
| Lung | 4.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 12.5 | High expression |
| MCF7 | 9.8 | Moderate expression |
| A549 | 7.2 | Moderate expression |
| HepG2 | 5.6 | Low expression |
| K562 | 4.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| R211W | Missense | 0.01% | Altered DNA binding affinity |
| S253A | Missense | Rare | Reduced phosphorylation, increased nuclear localization |
| T32A | Missense | Rare | Affects AKT-mediated regulation |
| G122S | Missense | 0.02% | Potential impact on protein stability |
| Deletion of 6q21 | Copy number loss | Variable | Loss of heterozygosity in cancers |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations or deletions reduce FOXO3 transcriptional activity, leading to impaired apoptosis and cell cycle arrest, contributing to cancer progression.
Gain of Function (GOF)
Gain-of-function mutations are rare but may enhance FOXO3 activity, potentially promoting longevity or increased stress resistance, though not commonly observed in disease.
Dominant Negative (DN)
Dominant-negative mutations can interfere with wild-type FOXO3 function, often by retaining the protein in the cytoplasm or disrupting DNA binding, leading to loss of tumor suppressor activity.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • protein kinase binding | • apoptotic process |
| • cell cycle arrest | • response to oxidative stress |
| • regulation of transcription by RNA polymerase II | • insulin receptor signaling pathway |
| • positive regulation of transcription by RNA polymerase II | • negative regulation of cell population proliferation |
Pathways
• PI3K-Akt signaling pathway
• FoxO signaling pathway
• Longevity regulating pathway
• AMPK signaling pathway
• Apoptosis
• Cell cycle
• Insulin signaling pathway
• mTOR signaling pathway
Protein Summary
FOXO3 is a 673-amino acid protein with a conserved forkhead DNA-binding domain. It functions as a transcription factor that regulates the expression of genes involved in apoptosis (e.g., BIM, PUMA), cell cycle inhibitors (p27, p21), antioxidant enzymes (MnSOD, catalase), and metabolic enzymes (G6Pase, PEPCK). Its activity is primarily regulated by AKT-mediated phosphorylation, which promotes cytoplasmic retention and inactivation. Under stress conditions, FOXO3 translocates to the nucleus to activate target genes. Post-translational modifications such as acetylation and ubiquitination further modulate its function. FOXO3 is a critical node in cellular stress response and longevity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FOXO3 Knockout HEK293 Cell Line | EDJ-KQ795 | Human | 2309 | Details Get a Quote |
| FOXO3 Knockout HCT 116 Cell Line | EDJ-KQ18283 | Human | 2309 | Details Get a Quote |
| FOXO3 Knockout A-549 Cell Line | EDJ-KQ19514 | Human | 2309 | Details Get a Quote |
| FOXO3 Knockout HeLa Cell Line | EDJ-KQ19516 | Human | 2309 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
