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ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress

Siim Pauklin1, Arnold Kristjuhan, Toivo Maimets

  • 1Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 23 Riia Street, Tartu 51010, Estonia. spauklin@ut.ee

Biochemical and Biophysical Research Communications
|July 12, 2005
PubMed

Insights

The tumor suppressor ARF and ATM/ATR kinase pathways cooperate to induce apoptosis when oncogenes like c-myc are overexpressed. This coordinated action is crucial for eliminating damaged cells.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Cancer research

Background:

  • Apoptosis is essential for removing cells with DNA damage or uncontrolled proliferation.
  • Oncogene activation can trigger cellular stress responses.
  • The ARF and ATM/ATR pathways are known regulators of cell cycle and survival.

Purpose of the Study:

  • To investigate the cooperative role of the ARF and ATM/ATR kinase pathways in oncogene-induced apoptosis.
  • To elucidate the molecular mechanisms underlying this cooperative process.

Main Methods:

  • Overexpression of oncogenes (c-myc, beta-catenin, HPV E7) and ARF.
  • Analysis of phosphorylated H2AX foci, Rad51 protein levels, and p53 phosphorylation.
  • Inhibition of ATM/ATR kinases.
  • Experiments in p53-deficient (p53-/-) cells.

Main Results:

  • Oncogene overexpression induced phosphorylated H2AX foci, Rad51, and ATM/ATR-dependent p53 phosphorylation.
  • ATM/ATR inhibition reduced Rad51 induction, p53 phosphorylation, and oncogene/ARF-induced apoptosis.
  • Apoptosis induction was impaired in p53-/- cells and independent of ATM/ATR activity.

Conclusions:

  • The tumor suppressor ARF and ATM/ATR kinase pathways cooperate to induce apoptosis in response to oncogene activation.
  • This process involves the regulation of p53 by both pathways.
  • Efficient oncogene-induced apoptosis relies on the coordinated action of ARF, ATM/ATR, and p53.

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