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Activation of p53 function by human transcriptional coactivator PC4: role of protein-protein interaction, DNA

Kiran Batta1, Tapas K Kundu

  • 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, P.O. Bangalore-560064, India.

Molecular and Cellular Biology
|September 6, 2007
PubMed

Insights

The transcriptional coactivator PC4 binds tumor suppressor p53, enhancing its DNA binding and gene activation. PC4 bends DNA, a crucial step for p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 is critical for cell cycle control and apoptosis.
  • p53's activity is modulated by various interacting proteins.
  • The transcriptional coactivator PC4 is known to interact with p53.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PC4 activates p53 function.
  • To investigate the role of PC4's DNA-binding domain in p53 regulation.
  • To understand how PC4-induced DNA bending influences p53 activity.

Main Methods:

  • In vivo and in vitro interaction studies between PC4 and p53.
  • Ligation-mediated circularization assays to assess DNA bending.
  • Deletion mutant analysis to identify critical domains for function.
  • Acetylation and phosphorylation studies on PC4.

Main Results:

  • PC4 binds to the DNA-binding and C-terminal domains of p53.
  • PC4 induces significant DNA bending, which is essential for stimulating p53 DNA binding.
  • PC4 mutants defective in DNA bending show impaired p53 activation.
  • PC4 acetylation enhances DNA bending and p53 activation, while phosphorylation abolishes it.
  • PC4 facilitates p53 recruitment to target gene promoters (Bax and p21).

Conclusions:

  • PC4 activates p53 function through direct interaction and by inducing DNA bending.
  • DNA bending by PC4 is a key mechanism for enhancing p53's DNA binding and transcriptional activity.
  • Post-translational modifications of PC4 (acetylation and phosphorylation) modulate its ability to regulate p53.
  • These findings reveal general mechanisms of p53 activation by coactivators.

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