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Oxidized DJ-1 inhibits p53 by sequestering p53 from promoters in a DNA-binding affinity-dependent manner

Izumi Kato1, Hiroshi Maita, Kazuko Takahashi-Niki

  • 1Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.

Molecular and Cellular Biology
|November 15, 2012
PubMed

Insights

Oxidized DJ-1 protein interacts with p53, affecting target gene expression. This interaction, dependent on DJ-1

Area of Science:

  • Molecular Biology
  • Oncology
  • Neuroscience

Background:

  • DJ-1 is implicated as an oncogene and in familial Parkinson's disease.
  • Oxidation of DJ-1 at cysteine 106 (C106) influences its functions, but mechanisms are unclear.
  • The role of DJ-1 in protein-protein interactions, particularly concerning p53, requires elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which DJ-1 oxidation affects its protein-protein interactions.
  • To determine how DJ-1 interacts with p53 and influences the expression of p53 target genes.
  • To clarify the role of DJ-1 oxidation at C106 in regulating gene expression and cellular processes like apoptosis.

Main Methods:

  • Co-immunoprecipitation assays to assess DJ-1 and p53 binding.
  • Reporter gene assays to measure DUSP1 and p21 promoter activity.
  • Western blotting to analyze protein levels and signaling pathways (e.g., ERK).
  • Cell culture experiments using DJ-1 knockout cells and transfected cell lines.

Main Results:

  • DJ-1 binding to p53 is dependent on the oxidation status of C106.
  • Oxidized DJ-1 sequesters p53 from the DUSP1 promoter, downregulating DUSP1 expression.
  • Downregulation of DUSP1 by oxidized DJ-1 activates ERK signaling and reduces apoptosis.
  • DJ-1 inhibits p21 promoter activity, particularly with p53 mutants of low DNA-binding affinity.

Conclusions:

  • DJ-1's interaction with p53 and subsequent regulation of target genes (DUSP1, p21) are critically dependent on DJ-1 oxidation at C106.
  • DJ-1 modulates p53 DNA-binding affinity and target gene expression, influencing cellular outcomes like apoptosis and ERK activation.
  • These findings provide molecular insights into DJ-1's dual role in oncogenesis and neurodegeneration.

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