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Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

Chiung-Min Wang1, William Harry Yang1, Leticia Cardoso1

  • 1Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.

International Journal of Molecular Sciences
|November 13, 2021
PubMed

Insights

Forkhead box P3 (FOXP3) regulates Activating Transcription Factor 3 (ATF3) expression, potentially impacting tumor development. Phosphorylation at Y342 on FOXP3 is crucial for this regulation, suggesting a new role for FOXP3 in cellular stress and cancer.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Activating transcription factor 3 (ATF3) is a stress-induced transcription factor vital for cellular stress response.
  • Forkhead box P3 (FOXP3) is an X-chromosome tumor suppressor that represses oncogenes.
  • The regulatory relationship between ATF3 and FOXP3 was previously unknown.

Purpose of the Study:

  • To investigate whether ATF3 is a target protein regulated by FOXP3.
  • To elucidate the role of post-translational modifications (PTMs) of FOXP3 in ATF3 regulation.
  • To identify the binding site of FOXP3 on the ATF3 promoter.

Main Methods:

  • Overexpression and siRNA knockdown of FOXP3 to assess ATF3 protein levels.
  • Luciferase reporter assays to measure ATF3 promoter activity.
  • Site-directed mutagenesis of FOXP3 to investigate PTMs' effects on ATF3 regulation.
  • Deletion and mutagenesis analysis of the ATF3 promoter to identify FOXP3 binding sites.

Main Results:

  • FOXP3 overexpression decreased ATF3 protein levels, while FOXP3 knockdown increased ATF3 expression.
  • FOXP3 dose-dependently repressed ATF3 promoter activity.
  • Phosphorylation mutation at Y342 in FOXP3 abolished ATF3 regulation, while other PTM mutations had no significant effect.
  • A specific FOXP3 binding site was identified on the ATF3 promoter.

Conclusions:

  • FOXP3 acts as a novel transcriptional regulator of ATF3.
  • FOXP3-mediated regulation of ATF3 is dependent on FOXP3 phosphorylation at Y342.
  • This newly identified regulatory mechanism may play a role in tumor development and progression.
Keywords:
ATF3FOXP3post-translational modificationtranscriptional activity

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