Description
FOXO4 Peptide – Technical Biochemical Mechanism Profile
(FOXO Transcription-Factor Interference Peptide; p53 Nuclear-Retention Modulator – Research Use Only)
FOXO4-interacting peptides are synthetic sequences designed to disrupt the protein-protein interaction between FOXO4 (Forkhead box O4 transcription factor) and p53 within senescent cell nuclei.
In vitro studies demonstrate selective interference with FOXO4-p53 binding motifs, altering downstream gene-expression programs involved in survival and senescence maintenance.
✅ 1. Primary Molecular Targets
| Target | Mechanistic Role |
|---|---|
| FOXO4 (Forkhead box O4) | Transcription factor controlling stress-response genes |
| p53 (TP53) | DNA-damage response and senescence regulator |
| FOXO4-p53 interface | Nuclear retention signal preventing p53-mediated apoptosis |
The peptide does not inhibit FOXO4 catalytic activity; instead, it interferes with the binding interface that keeps p53 localized in the nucleus of senescent cells.
✅ 2. Core Signaling Pathways
A. Transcription Factor Disruption
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FOXO4 normally tethers p53 to chromatin in senescent cells
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Interfering peptides block the FOXO4-CR3 / p53-DBD interaction
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p53 relocalizes away from nucleus in certain cellular models
B. Downstream Signal Cascades Monitored in Research
| Pathway | Observed Consequence in assays |
|---|---|
| p53 signaling | Altered expression of p21 (CDKN1A), GADD45, PUMA |
| FOXO signaling | Changes in FOXO-regulated oxidative stress genes |
| AKT/FOXO axis | FOXO phosphorylation → nuclear export modulation |
| JNK/FOXO activation | Stress-response transcriptional shifts |
✅ 3. Enzymes & Second Messengers
Although the peptide is not an enzyme, its pathway interacts with:
| Component | Role |
|---|---|
| AKT (PKB) | Phosphorylates FOXO → cytoplasmic retention |
| JNK | Phosphorylates FOXO under oxidative stress |
| SIRT1 | FOXO deacetylation and transcriptional control |
| ATM/ATR | DNA-damage signaling upstream of p53 |
| p38 MAPK | Senescence-associated transcription mediator |
These pathways regulate FOXO4 transcriptional activity and p53 stability.
✅ 4. Gene-Level Targets Commonly Monitored
| Functional Group | Representative Genes |
|---|---|
| Senescence & Cell-Cycle Arrest | CDKN1A (p21), CDKN2A (p16), GADD45, TP53, MDM2 |
| Apoptosis | BAX, PUMA (BBC3), BCL2L11 (BIM) |
| FOXO Oxidative Stress Response | SOD2, CAT, GADD45A, SESN1 |
| DNA-Damage Response | ATM, ATR, CHEK1/2 |
| SASP (senescence-associated secretory phenotype) | IL6, IL8, MMP1, MMP3, CXCL1 |
Changes in these markers are commonly measured in cell-based FOXO4 studies.
✅ 5. Structural/Mechanistic Features
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FOXO4 belongs to the Forkhead transcription factor family (FOXO1/3/4).
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Contains Forkhead DNA-binding domain, CR2, and CR3 interaction domain.
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FOXO4-CR3 directly binds p53-DNA binding domain to retain nuclear localization.
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Interference peptides bind FOXO4 to free p53.
This leads to:
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Nuclear export of p53
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Alteration of survival programs in senescent cell models
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Modulated SASP-linked transcription
✅ 6. Mechanistic Summary
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Synthetic peptide designed to disrupt FOXO4–p53 protein interactions
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Alters p53 nuclear retention in senescent cell research models
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Influences FOXO/AKT, MAPK, SIRT1, and DNA-damage pathways
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Affects transcription of p21, GADD45, PUMA, SOD2, IL-6, etc.
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Does not act as an enzyme or receptor agonist—acts through protein-interaction interference
✅ Research-Only Classification
FOXO4-Interacting Peptide is provided exclusively for in-vitro laboratory research.
Not approved for human or veterinary use, injection, ingestion, topical use, or any biological application.





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