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Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis

Hongjie Yao1, Pingxin Li, Bryan J Venters

  • 1Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.

The Journal of Biological Chemistry
|May 24, 2008
PubMed

Insights

The tumor suppressor gene OKL38 is activated by inhibiting PAD4 or activating p53 after DNA damage. OKL38 triggers apoptosis by releasing cytochrome c from mitochondria.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Protein Arg methyltransferases are coactivators of tumor suppressor p53, regulating gene expression.
  • Peptidylarginine deiminase 4 (PAD4) antagonizes methyltransferases through deimination and demethylimination.
  • Understanding the interplay between p53, PAD4, and gene regulation is crucial for cancer research.

Purpose of the Study:

  • To investigate the regulation of the tumor suppressor gene OKL38.
  • To elucidate the roles of p53 and PAD4 in OKL38 gene expression.
  • To determine the function of OKL38 in cellular processes, particularly apoptosis.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to assess protein occupancy and histone modifications.
  • DNA damage induction to study gene expression changes.
  • Mitochondrial localization studies and cytochrome c release assays.

Main Results:

  • OKL38 expression is activated by PAD4 inhibition or p53 activation following DNA damage.
  • p53 and PAD4 dynamically interact at the OKL38 promoter during DNA damage.
  • OKL38 localizes to mitochondria and induces cytochrome c release, triggering apoptosis.

Conclusions:

  • OKL38 is identified as a novel p53 target gene.
  • PAD4 regulates OKL38 expression, influencing its role in apoptosis.
  • OKL38 plays a significant role in initiating apoptosis via mitochondrial pathways.

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