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p53 Suppresses E2F1-dependent PLK1 expression upon DNA damage by forming p53-E2F1-DNA complex

Zhe Zhou1, Ji-Xiang Cao, Shu-Yan Li

  • 1Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100191, PR China.

Experimental Cell Research
|October 1, 2013
PubMed

Insights

The tumor suppressor p53 interacts with E2F1 to form a complex that represses polo-like kinase-1 (PLK1) gene expression, particularly after DNA damage. This p53-E2F1 interaction suppresses PLK1, promoting apoptosis and regulating cellular stress responses.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Polo-like kinase-1 (PLK1) is crucial for cell cycle progression and its suppression is vital for DNA damage checkpoints.
  • E2F1 is known to activate PLK1 transcription, but the regulatory mechanisms, especially under DNA damage, are not fully elucidated.
  • Previous studies indicated p53 can suppress PLK1 gene expression via direct promoter binding.

Purpose of the Study:

  • To investigate a novel mechanism by which p53 regulates E2F1-dependent PLK1 expression.
  • To elucidate the role of p53-E2F1 interaction in controlling PLK1 transcription in response to DNA damage.
  • To understand how this regulatory pathway contributes to apoptosis and cellular stress response.

Main Methods:

  • Co-transfection and reporter enzyme assays to assess PLK1 promoter activity.
  • Site-directed mutagenesis and deletion analysis of the PLK1 promoter to identify regulatory elements.
  • Co-immunoprecipitation and electrophoretic mobility shift assays (EMSA) to detect protein-DNA and protein-protein interactions.
  • Chromatin immunoprecipitation (ChIP) and re-ChIP assays to confirm in vivo complex formation.

Main Results:

  • p53 suppressed PLK1 gene activation, while E2F1 promoted it.
  • Specific E2F1 binding sites (-75/-68 and -40/-32) on the PLK1 promoter were essential for E2F1-mediated activation.
  • p53-mediated suppression of PLK1 was dependent on the E2F1 binding site at -40/-32, with complete abrogation upon its mutation.
  • DNA damage induced p53-E2F1 complex formation on the PLK1 promoter, confirmed by in vitro and in vivo assays.
  • Suppression of PLK1 by p53 was shown to promote apoptosis.

Conclusions:

  • p53 interacts with E2F1 to form a p53-E2F1-DNA complex that represses E2F1-driven PLK1 expression.
  • This novel mechanism highlights a p53-dependent regulation of E2F1 activity on the PLK1 gene during DNA damage.
  • The p53-E2F1-PLK1 pathway plays a significant role in mediating apoptosis and cellular response to DNA damage stress.
Keywords:
DNA damageE2F1PLK1Transcription regulationp53

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