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Plk1 regulates liver tumor cell death by phosphorylation of TAp63

S Komatsu1, H Takenobu, T Ozaki

  • 1Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba, Japan.

Oncogene
|August 12, 2009
PubMed

Insights

Polo-like kinase 1 (Plk1) phosphorylates and destabilizes TAp63, suppressing apoptosis in liver tumor cells. Inhibiting Plk1 reactivates TAp63, promoting cancer cell death and offering a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • Polo-like kinase 1 (Plk1) is known to inhibit p53/p73 activity via phosphorylation.
  • The role of Plk1 in modulating the p53 family member TAp63 in liver tumor cells remains to be fully elucidated.

Purpose of the Study:

  • To investigate the functional role of Plk1 in regulating TAp63 activity and its impact on apoptotic cell death in liver tumor cells.
  • To explore the potential of the Plk1/TAp63 interaction as a therapeutic target for liver cancer.

Main Methods:

  • Immunoprecipitation and in vitro pull-down assays to determine Plk1-p63 binding.
  • In vitro kinase assays to identify phosphorylation sites.
  • Plk1 knockdown experiments in liver tumor cells.
  • Analysis of downstream effector gene expression (PUMA, p21, 14-3-3sigma).
  • Flow cytometry to assess apoptotic cell death.
  • Side population (SP) cell analysis.

Main Results:

  • Plk1 directly binds to the DNA-binding region of p63.
  • Plk1 phosphorylates p63 at Ser-52 in the transactivating (TA) domain, decreasing TAp63 protein stability and suppressing TAp63-induced cell death.
  • Plk1 knockdown in p53-mutated liver tumor cells reactivates p53 family downstream effectors and induces apoptosis.
  • Double knockdown of Plk1 and p63 attenuates Plk1 knockdown-induced apoptosis.
  • Both Plk1 and p63 are highly expressed in the tumor-initiating side population (SP) cells.

Conclusions:

  • Plk1 regulates TAp63 stability and activity through phosphorylation, thereby controlling apoptotic cell death in liver tumor cells.
  • The Plk1/TAp63 pathway is crucial in regulating cell death, particularly in tumor-initiating SP cells.
  • Targeting Plk1/TAp63 represents a promising therapeutic strategy for liver tumor treatment.

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