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Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance

Yiping Huang1, Jun Seop Jeong, Jun Okamura

  • 1Department of Dermatology, Institute of Basic Biomedical Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cell Cycle (Georgetown, Tex.)
|June 8, 2012
PubMed

Insights

Phosphorylation of the tumor protein p63 (p63) is crucial for cisplatin sensitivity in squamous cell carcinoma. Non-phosphorylated p63 promotes cisplatin resistance by altering mRNA splicing and cell death pathways.

Area of Science:

  • Molecular oncology
  • Cancer cell biology
  • Proteomics

Background:

  • Cisplatin chemoresistance is a significant challenge in treating epithelial cancers.
  • The tumor protein p53 family, including p63, plays a role in chemoresistance mechanisms.
  • The precise cellular responses to cisplatin-induced cell death remain under investigation.

Purpose of the Study:

  • To elucidate the role of p63 phosphorylation in cisplatin chemoresistance in squamous cell carcinoma (SCC).
  • To investigate the protein-protein interactions of TP53 and ΔNp63α in response to cisplatin.
  • To understand how p63 phosphorylation affects mRNA splicing and cell death pathways.

Main Methods:

  • Quantitative mass spectrometry using isobaric tags to analyze protein complexes.
  • Investigating ATM-dependent phosphorylation of ΔNp63α.
  • Analyzing the impact of phosphorylated (p)-ΔNp63α and non-phosphorylated (non-p)-ΔNp63α-S385G on splicing and cell death.

Main Results:

  • Phosphorylation of ΔNp63α by ATM is critical for cisplatin sensitivity in SCC cells.
  • SCC cells expressing non-p-ΔNp63α-S385G exhibit cisplatin resistance.
  • p-ΔNp63α interacts with the splicing complex, repressing mRNA splicing and activating the ACIN1 cell death pathway.
  • Non-p-ΔNp63α fails to bind splicing complex members, leading to activated RNA splicing and reduced cell death.

Conclusions:

  • The p53/p63 interactome is implicated in cisplatin chemoresistance.
  • Phosphorylation status of ΔNp63α dictates its interaction with the splicing machinery, controlling cell fate.
  • Targeting p63 phosphorylation or its interactions may offer strategies to overcome cisplatin resistance.

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