The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein

Michela Muscolini, Elisa Montagni, Vanessa Palermo, Silvia Di Agostino, Wei Gu, Salma Abdelmoula-Souissi, Cristina Mazzoni, Giovanni Blandino, Loretta Tuosto

Research output: Contribution to journalArticle

Abstract

Stress-induced monoubiquitination of p53 is a crucial event for the nuclear-cytoplasm-mitochondria trafficking and transcription- independent pro-apoptotic functions of p53. Although an intact ubiquitination pathway and a functional nuclear export sequence are required for p53 nuclear export, the role of specific residues within this region in regulating both processes remains largely unknown. Here we characterize the mechanisms accounting for the nuclear accumulation of a new point mutation (Lys-351 to Asn) in the nuclear export sequence of p53 identified in a cisplatin-resistant ovarian carcinoma cell line (A2780 CIS). We found that K351N substitution abrogates the monoubiquitination of p53 induced by both Mdm2 and MSL2 E3-ligases. As a consequence, cells expressing p53 K351N mutant showed defects in cisplatin-induced translocation of p53 to mitochondria, Bax oligomerization, and mitochondrial membrane depolarization. These data identify K351N as a critical mutation of p53 that contributes to the development and maintenance of resistance to cisplatin.

Original languageEnglish
Pages (from-to)39693-39702
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number46
DOIs
Publication statusPublished - Nov 18 2011

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Mitochondria
Cell Nucleus Active Transport
Ubiquitination
Cisplatin
Mutation
Cells
Neoplasms
Oligomerization
Proteins
Ubiquitin-Protein Ligases
Depolarization
Mitochondrial Membranes
Transcription
Point Mutation
Cytoplasm
Substitution reactions
Maintenance
Membranes
Carcinoma
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Muscolini, M., Montagni, E., Palermo, V., Di Agostino, S., Gu, W., Abdelmoula-Souissi, S., ... Tuosto, L. (2011). The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein. Journal of Biological Chemistry, 286(46), 39693-39702. https://doi.org/10.1074/jbc.M111.279539

The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein. / Muscolini, Michela; Montagni, Elisa; Palermo, Vanessa; Di Agostino, Silvia; Gu, Wei; Abdelmoula-Souissi, Salma; Mazzoni, Cristina; Blandino, Giovanni; Tuosto, Loretta.

In: Journal of Biological Chemistry, Vol. 286, No. 46, 18.11.2011, p. 39693-39702.

Research output: Contribution to journalArticle

Muscolini, M, Montagni, E, Palermo, V, Di Agostino, S, Gu, W, Abdelmoula-Souissi, S, Mazzoni, C, Blandino, G & Tuosto, L 2011, 'The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein', Journal of Biological Chemistry, vol. 286, no. 46, pp. 39693-39702. https://doi.org/10.1074/jbc.M111.279539
Muscolini, Michela ; Montagni, Elisa ; Palermo, Vanessa ; Di Agostino, Silvia ; Gu, Wei ; Abdelmoula-Souissi, Salma ; Mazzoni, Cristina ; Blandino, Giovanni ; Tuosto, Loretta. / The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 46. pp. 39693-39702.
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