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Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73

Hiroshi Katayama1, Jin Wang, Warapen Treekitkarnmongkol

  • 1Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.

Cancer Cell
|February 21, 2012
PubMed

Insights

Aurora kinase-A phosphorylates p73, leading to its cytoplasmic sequestration and abrogating DNA damage responses. This mechanism contributes to tumor cell survival by overriding the mitotic spindle assembly checkpoint (SAC).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Biology

Background:

  • Aurora kinase-A is implicated in cell proliferation and cancer progression.
  • The p73 protein is a tumor suppressor involved in apoptosis and cell cycle control.
  • The mitotic spindle assembly checkpoint (SAC) prevents aneuploidy by delaying cell cycle progression until all chromosomes are properly attached to the spindle.

Purpose of the Study:

  • To investigate the role of Aurora kinase-A in regulating p73 function.
  • To elucidate the mechanism by which Aurora kinase-A contributes to tumor cell survival and resistance to apoptosis.
  • To determine the impact of Aurora kinase-A-mediated p73 modification on SAC regulation.

Main Methods:

  • Western blotting to detect protein phosphorylation and complex formation.
  • Immunofluorescence microscopy to assess protein localization.
  • Cell viability assays and apoptosis assays (e.g., using cisplatin treatment).
  • Analysis of SAC component dynamics (e.g., MAD2-CDC20 complex) during mitosis.

Main Results:

  • Aurora kinase-A phosphorylates p73 at serine235, leading to its cytoplasmic sequestration with mortalin.
  • Phosphorylation abrogates p73's transactivation function and promotes SAC override by dissociating the MAD2-CDC20 complex.
  • Cells expressing a phosphor-mimetic p73 mutant exhibit resistance to cisplatin-induced apoptosis and premature mitotic exit.
  • Elevated cytoplasmic p73 is observed in human tumors overexpressing Aurora kinase-A.

Conclusions:

  • Aurora kinase-A-mediated p73 phosphorylation is a key mechanism for tumor cell survival.
  • This modification contributes to resistance to DNA damage-induced apoptosis and SAC override.
  • Targeting Aurora kinase-A or its interaction with p73 may represent a therapeutic strategy for cancer treatment.

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