Plk1-mediated phosphorylation of Topors regulates p53 stability

J Biol Chem. 2009 Jul 10;284(28):18588-92. doi: 10.1074/jbc.C109.001560. Epub 2009 May 27.

Abstract

Polo-like kinase 1 (Plk1) overexpression is associated with tumorigenesis by an unknown mechanism. Likewise, Plk1 was suggested to act as a negative regulator of tumor suppressor p53, but the mechanism remains to be determined. Herein, we have identified topoisomerase I-binding protein (Topors), a p53-binding protein, as a Plk1 target. We show that Plk1 phosphorylates Topors on Ser(718) in vivo. Significantly, expression of a Plk1-unphosphorylatable Topors mutant (S718A) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (SUMO E3) ligase. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Genes, p53*
  • Humans
  • Models, Biological
  • Mutation
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Polo-Like Kinase 1
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • TOPORS protein, human
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases