IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60844-9.html
   My bibliography  Save this article

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

Author

Listed:
  • Benjamin Bourgeois

    (Medical University of Graz)

  • Emil Spreitzer

    (Medical University of Graz)

  • Daniel Platero-Rochart

    (Medical University of Graz)

  • Margret Paar

    (Medical University of Graz)

  • Qishun Zhou

    (Medical University of Graz)

  • Sinem Usluer

    (Medical University of Graz)

  • Peter L. J. Keizer

    (Utrecht University
    Cleara Biotech B.V.)

  • Boudewijn M. T. Burgering

    (Utrecht University)

  • Pedro A. Sánchez-Murcia

    (Medical University of Graz
    BioTechMed-Graz)

  • Tobias Madl

    (Medical University of Graz
    BioTechMed-Graz)

Abstract

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.

Suggested Citation

  • Benjamin Bourgeois & Emil Spreitzer & Daniel Platero-Rochart & Margret Paar & Qishun Zhou & Sinem Usluer & Peter L. J. Keizer & Boudewijn M. T. Burgering & Pedro A. Sánchez-Murcia & Tobias Madl, 2025. "The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60844-9
    DOI: 10.1038/s41467-025-60844-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60844-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60844-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60844-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.