FOXO4: Forkhead Box O4 - A Key Regulator of Cellular Senescence and Apoptosis
Comprehensive genomic and proteomic analysis of FOXO4, a transcription factor implicated in aging, cancer, and stress resistance.
Gene Information Card
| Symbol | FOXO4 |
|---|---|
| Full Name | Forkhead Box O4 |
| Gene Type | Protein coding |
| Chromosomal Location | Xq13.1 |
| NCBI Gene ID | 4303 ncbi.nlm.nih.gov/gene/4303 |
| Ensembl ID | ENSG00000184481 |
| UniProt ID | P98177 |
| OMIM ID | 300033 |
| HGNC ID | 3819 |
| Aliases | AFX, MLLT7, FOXO4A, FOXO4B |
Description
FOXO4 (Forkhead Box O4) is a member of the forkhead box O (FOXO) family of transcription factors. It regulates gene expression involved in cellular processes such as apoptosis, cell cycle arrest, DNA repair, oxidative stress resistance, and metabolism. FOXO4 is a downstream effector of the PI3K/AKT signaling pathway and is implicated in aging, longevity, and tumor suppression. Its activity is modulated by post-translational modifications including phosphorylation, acetylation, and ubiquitination.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Acute Myeloid Leukemia (AML) | FOXO4 is fused to MLL in t(X;11)(q13;q23) translocations, leading to oncogenic chimeric proteins. | PMID: 10655554; COSMIC |
| Prostate Cancer | FOXO4 loss or inactivation promotes tumor progression via reduced apoptosis and increased proliferation. | PMID: 17016423; NCBI |
| Rhabdomyosarcoma | FOXO4 expression is altered in alveolar rhabdomyosarcoma due to PAX3/PAX7-FOXO4 fusions. | PMID: 12460918; COSMIC |
| Aging and Senescence | FOXO4-p53 interaction mediates cellular senescence; FOXO4 inhibition reverses senescence in aged mice. | PMID: 28871086; NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal Muscle | 12.5 | Medium |
| Heart | 10.2 | Medium |
| Brain | 8.7 | Low |
| Liver | 6.3 | Low |
| Kidney | 7.1 | Low |
| Lung | 9.8 | Medium |
| Testis | 15.3 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.2 | Embryonic kidney cells; high expression |
| HeLa | 11.5 | Cervical cancer cells; moderate expression |
| MCF7 | 9.8 | Breast cancer cells; moderate expression |
| K562 | 7.3 | Leukemia cells; low expression |
| HepG2 | 8.1 | Liver cancer cells; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Ser193Ala | Missense | <0.1% | Alters AKT phosphorylation site; reduces nuclear export |
| p.Thr32Ala | Missense | <0.1% | Disrupts AKT-mediated phosphorylation; increases transcriptional activity |
| p.Arg211* | Nonsense | <0.1% | Truncation; loss of DNA-binding domain |
| p.Glu175Lys | Missense | <0.1% | Impairs FOXO4-p53 interaction; reduces senescence induction |
Mutation functional classification
Loss of Function (LOF)
Nonsense mutations (e.g., p.Arg211*) and frameshift deletions that truncate the forkhead domain or transactivation domain lead to loss of transcriptional activity.
Gain of Function (GOF)
Missense mutations at AKT phosphorylation sites (e.g., p.Thr32Ala, p.Ser193Ala) prevent nuclear export, resulting in constitutive nuclear localization and enhanced target gene activation.
Dominant Negative (DN)
Mutations that disrupt DNA binding (e.g., in the forkhead domain) but retain protein-protein interaction domains can sequester wild-type FOXO4 or cofactors, inhibiting normal function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• PI3K/AKT Signaling Pathway
• FOXO-mediated Transcription
• Cellular Senescence Pathway
• Apoptosis Pathway
• Insulin/IGF-1 Signaling Pathway
• Oxidative Stress Response Pathway
Protein Summary
FOXO4 is a 505-amino acid transcription factor containing a conserved forkhead DNA-binding domain. It shuttles between the nucleus and cytoplasm in response to AKT phosphorylation. In the nucleus, FOXO4 activates genes involved in apoptosis (e.g., BIM, FASL), cell cycle arrest (e.g., p27Kip1, GADD45), and stress resistance (e.g., SOD2, catalase). FOXO4 also interacts with p53 to promote cellular senescence. Post-translational modifications such as acetylation by p300/CBP and deacetylation by SIRT1 modulate its activity. FOXO4 is a potential therapeutic target for aging-related diseases and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FOXO4 Knockout HEK293 Cell Line | EDJ-KQ1242 | Human | 4303 | Details Get a Quote |
| FOXO4 Knockout A-549 Cell Line | EDJ-KQ19239 | Human | 4303 | Details Get a Quote |
| FOXO4 Knockout HCT 116 Cell Line | EDJ-KQ20600 | Human | 4303 | Details Get a Quote |
| FOXO4 Knockout HeLa Cell Line | EDJ-KQ20601 | Human | 4303 | Details Get a Quote |
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