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The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response

Hongwu Zheng1, Han You, Xiao Zhen Zhou

  • 1Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Nature
|October 25, 2002
PubMed

Insights

DNA damage triggers p53 activation through phosphorylation and interaction with Pin1, a peptidyl-prolyl isomerase. This interaction enhances p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 plays a crucial role in cellular responses to genotoxic stress, mediating cell cycle arrest and apoptosis.
  • While DNA damage is known to activate p53 through phosphorylation, the precise mechanisms of p53 activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which DNA damage activates p53.
  • To investigate the role of peptidyl-prolyl isomerase Pin1 in p53 regulation.

Main Methods:

  • Analysis of p53 phosphorylation on Ser/Thr-Pro motifs following DNA damage.
  • Assessment of the interaction between p53 and Pin1.
  • Functional assays to evaluate p53 DNA-binding and transactivation activities.
  • Studies using Pin1-deficient cells to assess p53 activation and DNA damage response.

Main Results:

  • DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, creating a binding site for Pin1.
  • Pin1 binds to phosphorylated p53, enhancing its DNA-binding and transactivation functions.
  • Pin1-mediated p53 activation requires its WW domain and isomerase activity.
  • Pin1-deficient cells show impaired p53 activation, delayed p53 protein accumulation, and defective DNA damage checkpoint control.

Conclusions:

  • DNA damage-induced p53 phosphorylation facilitates its interaction with Pin1, a key regulator of p53 activity.
  • Pin1 acts as a crucial activator of p53's tumor-suppressive functions by enhancing its DNA-binding and transcriptional activity.
  • These findings reveal a novel mechanism for p53 regulation in response to genotoxic stress, highlighting Pin1 as a critical component of the DNA damage response pathway.

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