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Updated: Sep 25, 2025

Preparation of Cell-lines for Conditional Knockdown of Gene Expression and Measurement of the Knockdown Effects on E4orf4-Induced Cell Death
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FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

Raju Mandal1, Klara Kohoutova1,2, Olivia Petrvalska1,2

  • 1Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.

Protein Science : a Publication of the Protein Society
|April 28, 2022
PubMed

Insights

The tumor suppressor p53 protein interacts with FOXO4, a transcription factor, to induce cellular senescence. Structural analysis reveals key interactions stabilizing the p53:FOXO4 complex and blocking p53 DNA binding.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • The transcription factor p53 is a critical tumor suppressor, activated by cellular stress.
  • p53 interacts with Forkhead box O (FOXO) 4 to promote cellular senescence via p21 upregulation.
  • The structural basis of the p53-FOXO4 interaction and its functional consequences are not well understood.

Purpose of the Study:

  • To elucidate the structural details of the interaction between transcription factors p53 and FOXO4.
  • To understand how this interaction influences protein complex stability and DNA-binding activity.
  • To provide insights into the roles of p53 and FOXO4 in cellular homeostasis and stress response.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Chemical cross-linking experiments.
  • Analytical ultracentrifugation.

Main Results:

  • The interaction between the p53 Transactivation Domain (TAD) and the FOXO4 Forkhead domain is crucial for p53:FOXO4 complex stability.
  • Stabilization of the complex involves contacts between FOXO4's N-terminal segment, p53's C-terminal negative regulatory domain, and both proteins' DNA-binding domains.
  • Complex formation inhibits p53's DNA binding without altering FOXO4's DNA-binding capacity.

Conclusions:

  • Structural characterization reveals critical interfaces governing the p53-FOXO4 interaction.
  • The p53:FOXO4 complex formation modulates p53's DNA-binding activity, impacting cellular stress responses.
  • Findings contribute to understanding the coordinated functions of p53 and FOXO4 in maintaining cellular integrity and longevity.
Keywords:
DNA bindingForkhead box O 4nuclear magnetic resonanceprotein-protein interactionsenescencetranscription factor p53

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