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Regulation of protein Citrullination through p53/PADI4 network in DNA damage response

Chizu Tanikawa1, Koji Ueda, Hidewaki Nakagawa

  • 1Laboratory of Molecular Medicine, Human Genome Center, Division of Gene Expression and Regulation, Institute of Medical Science, the University of Tokyo, Japan.

Cancer Research
|October 22, 2009
PubMed

Insights

The tumor suppressor p53 regulates protein citrullination by activating peptidylarginine deiminase type 4 (PADI4). This p53/PADI4 pathway influences protein localization and inhibits tumor cell growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor p53 is crucial for inhibiting malignant transformation via transcriptional regulation of target genes.
  • The role of p53 in protein posttranslational modifications, specifically citrullination, remains largely uncharacterized.

Purpose of the Study:

  • To investigate the novel role of p53 in regulating protein citrullination.
  • To elucidate the mechanism by which p53 influences citrullination and its impact on cellular processes.

Main Methods:

  • Assessed p53-mediated transactivation of peptidylarginine deiminase type 4 (PADI4) using p53-binding site analysis.
  • Utilized ectopic expression and knockdown experiments to evaluate the impact of p53 and PADI4 on protein citrullination.
  • Investigated the citrullination of nucleophosmin (NPM1) by PADI4 in vivo and its effect on protein localization.

Main Results:

  • p53 directly transactivates PADI4, an enzyme that catalyzes protein citrullination.
  • p53 and PADI4 are essential for DNA damage-induced protein citrullination, demonstrating a p53/PADI4-dependent regulation.
  • PADI4 citrullinates NPM1 at arginine 197, causing its translocation from nucleoli to nucleoplasm.
  • PADI4 expression inhibits tumor cell growth, and PADI4 knockdown attenuates p53-mediated growth inhibition.

Conclusions:

  • p53 plays a novel role in regulating protein citrullination through the PADI4 pathway.
  • PADI4-mediated citrullination of NPM1 is a key event in the p53 signaling pathway, impacting cellular localization and tumor growth.
  • This study highlights the significance of protein citrullination in p53-dependent tumor suppression.

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