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 language | English |
|---|---|
| Pages (from-to) | 39693-39702 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 286 |
| Issue number | 46 |
| DOIs | |
| Publication status | Published - Nov 18 2011 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
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 journal › Article
}
TY - JOUR
T1 - The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein
AU - Muscolini, Michela
AU - Montagni, Elisa
AU - Palermo, Vanessa
AU - Di Agostino, Silvia
AU - Gu, Wei
AU - Abdelmoula-Souissi, Salma
AU - Mazzoni, Cristina
AU - Blandino, Giovanni
AU - Tuosto, Loretta
PY - 2011/11/18
Y1 - 2011/11/18
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=81155154333&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.279539
DO - 10.1074/jbc.M111.279539
M3 - Article
C2 - 21953469
AN - SCOPUS:81155154333
VL - 286
SP - 39693
EP - 39702
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 46
ER -