PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells

Debora Russo, Laura Ottaggio, Ilaria Penna, Giorgia Foggetti, Gilberto Fronza, Alberto Inga, Paola Menichini

Research output: Contribution to journalArticle

Abstract

PRIMA-1 has been identified as a compound that restores the transactivation function to mutant p53 and induces apoptosis in cells expressing mutant p53. Studies on subcellular distribution of the mutant p53 protein upon treatment with PRIMA-1Met, a methylated form of PRIMA-1, have suggested that redistribution of mutant p53 to nucleoli may play a role in PRIMA-1 induced apoptosis. Here, we specifically investigated the influence of PRIMA-1 on cellular localization of mutated p53-R280K endogenously expressed in tumour cells. By using immunofluorescence staining, we found a strong nucleolar redistribution of mutant p53 following PRIMA-1 treatment. This subcellular localization was associated to p53 degradation via ubiquitylation. When cells were treated with adriamycin, neither nucleolar redistribution nor mutant p53 down modulation and degradation were observed. Interestingly, cells where p53-R280K was silenced were more sensitive to PRIMA-1 than the parental ones. These results indicate that in some cellular context, the cell sensitivity to PRIMA-1 could depend on the abolition of a gain-of-function activity of the mutated p53, through a protein degradation pathway specifically induced by this compound.

Original languageEnglish
Pages (from-to)345-350
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume402
Issue number2
DOIs
Publication statusPublished - Nov 12 2010

Keywords

  • Breast cancer
  • Mutant p53
  • Nucleolus
  • P53 degradation
  • P53 ubiquitylation
  • PRIMA-1

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

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