title: The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein.
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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University, 00185-Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Muscolini
authors.forename: Elisa
authors.initials: E
authors.lastname: Montagni
authors.forename: Vanessa
authors.initials: V
authors.lastname: Palermo
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Agostino
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Salma
authors.initials: S
authors.lastname: Abdelmoula-Souissi
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazzoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.forename: Loretta
authors.initials: L
authors.lastname: Tuosto
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D049790:Nuclear Export Signals / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D049790:Nuclear Export Signals; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; C560942:MSL2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin