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The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage

J G Gong1, A Costanzo, H Q Yang

  • 1Department of Biology, University of California, San Diego, La Jolla 92093-0322, USA.

Nature
|July 3, 1999
PubMed

Insights

Cisplatin chemotherapy activates a DNA repair-dependent cell death pathway involving p73 and c-Abl tyrosine kinase. This pathway enhances cancer cell killing, even in the absence of the tumor suppressor p53.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • Chemotherapy agents like cisplatin induce cancer cell death via DNA damage and apoptosis.
  • The tumor suppressor p53 is a key apoptosis activator, but p53-deficient cells retain some chemotherapy sensitivity, suggesting alternative pathways.
  • The p53-related gene p73 also induces apoptosis and may play a role in chemotherapy response.

Purpose of the Study:

  • To investigate the role of p73 and its regulation in cisplatin-induced apoptosis.
  • To identify mechanisms contributing to chemotherapy resistance in p53-deficient cancer cells.
  • To elucidate the involvement of DNA mismatch repair and c-Abl tyrosine kinase in cisplatin cytotoxicity.

Main Methods:

  • Treating cancer cells with cisplatin and analyzing p73 protein levels.
  • Investigating the effect of mismatch repair deficiency and c-Abl inhibition on p73 induction.
  • Assessing the impact of c-Abl tyrosine kinase on p73 stability and function.
  • Comparing cisplatin sensitivity in mouse embryo fibroblasts with and without mismatch repair or c-Abl.

Main Results:

  • Cisplatin treatment increases p73 protein levels in a manner dependent on mismatch repair and c-Abl activation.
  • The half-life and apoptosis-inducing function of p73 are enhanced by cisplatin and c-Abl tyrosine kinase.
  • Cells deficient in mismatch repair or c-Abl show reduced p73 upregulation and increased resistance to cisplatin.
  • p73 protein is stabilized and activated by c-Abl tyrosine kinase.

Conclusions:

  • Cisplatin induces apoptosis through a pathway involving p73 and c-Abl tyrosine kinase.
  • This pathway is dependent on DNA mismatch repair, contributing to cisplatin cytotoxicity.
  • Understanding this p73/c-Abl axis offers insights into chemotherapy resistance and potential therapeutic strategies.

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