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p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1

Surinder M Soond1, Sean P Barry, Gerry Melino

  • 1Medical Molecular Biology Unit, Institute of Child Health, University College London, London, United Kingdom. s.soond@ich.ucl.ac.uk

Cell Cycle (Georgetown, Tex.)
|April 18, 2008
PubMed

Insights

Polo-Like Kinase 1 (PLK1) phosphorylates the p53 family member TAp73, deactivating its transcriptional activity. This PLK1-mediated phosphorylation of TAp73 at Threonine-27 is a key step in abrogating gene activation in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The p53 family member trans-activating (TA) p73 regulates genes involved in cell cycle control and apoptosis.
  • TAp73 is paradoxically overexpressed in some tumors, suggesting post-translational modifications regulate its activity.

Purpose of the Study:

  • To investigate the interaction between TAp73 and Polo-Like Kinase 1 (PLK1).
  • To determine if PLK1 affects TAp73's transcriptional activity through phosphorylation.

Main Methods:

  • Co-localization and interaction studies between TAp73 and PLK1.
  • Reporter assays and Electrophoretic Mobility Shift Assays (EMSA) to assess TAp73's effect on gene promoters.
  • Analysis of TAp73 phosphorylation at Threonine-27 (Thr-27).

Main Results:

  • TAp73 interacts with and co-localizes with PLK1.
  • PLK1 phosphorylates TAp73 at Thr-27 within the TA domain.
  • PLK1 abrogates TAp73-mediated activation of p21(cip/waf), 14-3-3sigma, and Bax gene promoters.
  • Phosphorylation of TAp73 Thr-27 is crucial for this deactivation in MCF7 cells.

Conclusions:

  • PLK1 directly regulates TAp73 transcriptional activity via phosphorylation at Thr-27.
  • This mechanism represents a novel pathway for PLK1-mediated transcriptional deactivation of TAp73.
  • Understanding this interaction could reveal new therapeutic strategies for cancers with TAp73 overexpression.

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