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Study · In vitro (cell-free) · 2025

3 results

The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.

Bourgeois B, Spreitzer E, Platero-Rochart D, Paar M, Zhou Q, Usluer S, de Keizer PLJ, Burgering BMT, Sánchez-Murcia PA, Madl T

Nature communications1 Jul 2025Cited by 17 (Europe PMC)

PMID40593617 (opens in a new tab)PMCIDPMC12216184 (opens in a new tab)DOI10.1038/s41467-025-60844-9 (opens in a new tab)PepBankPUB-40593617
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Summary

A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 - p53 axis as pivotal in maintaining the viability of senescent cells, and that senescent cells can be targeted selectively with the senolytic peptide FOXO4-DRI. Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI. Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53TAD2 and forms a transiently folded complex. In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction. Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI. Summarizing we provide a detailed characterization of the interaction of p53 with FOXO4 and FOXO4-DRI which is the basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01LabIn vitro (cell-free)Activity measurement

    In vitro, p53 phosphorylation increased the binding affinity for FOXO4‑DRI.

    In plain wordsIn lab tests, FOXO4‑DRI bound phosphorylated p53 more strongly.

    Peptide
    FOXO4-DRI
    Outcome
    IncreaseAffinity of FOXO4-DRI for p53 with phosphorylation
    Study

    n: not reported in source

    Solution NMR structural models
    Outcome group
    Receptor activity and mechanism · Aging and longevity
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI.
    1 context sentence
    Summary · context
    Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI.

Studies that did not test the peptide alone2

In this study, FOXO4-DRI was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking FOXO4-DRI.

  1. 02LabNot a test of FOXO4-DRI aloneIn vitro (cell-free)Activity measurement

    In NMR structural models, disordered FOXO4‑DRI bound the disordered p53 TAD2 and formed a transiently folded complex.

    In plain wordsIn lab tests, FOXO4‑DRI bound a part of p53 and formed a complex that is briefly folded.

    Peptide
    FOXO4-DRI
    Outcome
    Not applicableBinding of FOXO4-DRI to p53 TAD2
    Study

    n: not reported in source

    Solution NMR structural models
    Outcome group
    Receptor activity and mechanism · Aging and longevity

    Source sentences

    Summary
    Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53TAD2 and forms a transiently folded complex.
    1 context sentence
    Summary · context
    Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI.

    In this study, FOXO4-DRI was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking FOXO4-DRI.

  2. 03LabNot a test of FOXO4-DRI aloneIn vitro (cell-free)Mechanism

    In the FOXO4‑DRI and p53 TAD2 complex, both the FOXO4-derived region and the cationic cell permeability peptide contributed to the interaction.

    In plain wordsIn lab tests, two parts of FOXO4‑DRI both helped it bind p53.

    Peptide
    FOXO4-DRI
    Outcome
    Not applicableRegions of FOXO4-DRI that contribute to the interaction
    Study

    n: not reported in source

    Solution NMR structural models
    Outcome group
    Receptor activity and mechanism · Aging and longevity

    Source sentences

    Summary
    In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction.
    1 context sentence
    Summary · context
    Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI.

    In this study, FOXO4-DRI was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking FOXO4-DRI.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    13 Oct 2026, 21:44 UTC

    Study results updated

  2. Version 1

    13 Oct 2026, 16:31 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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