Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215

Qiyuan Liu1, Satoshi Kaneko, Lin Yang

  • 1Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.

Insights

The mitotic kinase Aurora-A phosphorylates tumor suppressor p53 at Serine 215, inactivating its DNA binding and transactivation functions. This Aurora-A mediated p53 inactivation overrides apoptosis and cell cycle arrest signals.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • The tumor suppressor p53 is a critical regulator of cell cycle arrest and apoptosis in response to cellular stress.
  • Posttranslational modifications and protein interactions modulate p53 stability and activity.
  • The mitotic kinase Aurora-A has been implicated in cell cycle regulation.

Purpose of the Study:

  • To investigate the interaction between Aurora-A and p53.
  • To determine the functional consequence of p53 phosphorylation by Aurora-A.
  • To elucidate the role of Aurora-A in regulating p53-mediated cellular responses.

Main Methods:

  • Site-directed mutagenesis to create phosphomimic (S215D) and non-phosphorylatable (S215A) p53 mutants.
  • Western blotting to detect p53 phosphorylation.
  • DNA binding assays to assess p53's transcriptional activity.
  • Cell-based assays to evaluate apoptosis and cell cycle arrest.

Main Results:

  • Aurora-A directly phosphorylates p53 at Serine 215.
  • Phosphorylation of p53 at Ser-215 by Aurora-A abrogates p53 DNA binding and transactivation activity.
  • Aurora-A overrides cisplatin-induced apoptosis and gamma-irradiation-induced cell cycle arrest in a Ser-215 dependent manner.
  • Phosphorylation at Ser-315 does not affect Aurora-A's impact on p53 function.

Conclusions:

  • Phosphorylation of p53 at Ser-215 by Aurora-A is a key mechanism for p53 inactivation.
  • Aurora-A's regulation of p53 provides molecular insight into Aurora-A's broader functions in cell cycle control and tumor suppression evasion.

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