TY - JOUR
T1 - Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer
AU - Sonego, Maura
AU - Schiappacassi, Monica
AU - Lovisa, Sara
AU - Dall'Acqua, Alessandra
AU - Bagnoli, Marina
AU - Lovat, Francesca
AU - Libra, Massimo
AU - D'Andrea, Sara
AU - Canzonieri, Vincenzo
AU - Militello, Loredana
AU - Napoli, Marco
AU - Giorda, Giorgio
AU - Pivetta, Barbara
AU - Mezzanzanica, Delia
AU - Barbareschi, Mattia
AU - Valeri, Barbara
AU - Canevari, Silvana
AU - Colombatti, Alfonso
AU - Belletti, Barbara
AU - Del Sal, Giannino
AU - Baldassarre, Gustavo
PY - 2013/5
Y1 - 2013/5
N2 - Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA-PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53MUT-dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
AB - Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA-PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53MUT-dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
KW - Carboplatinum
KW - DNA-PK
KW - Mutant p53
KW - Ovarian cancer
KW - Stathmin
UR - http://www.scopus.com/inward/record.url?scp=84877336712&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877336712&partnerID=8YFLogxK
U2 - 10.1002/emmm.201201504
DO - 10.1002/emmm.201201504
M3 - Article
C2 - 23610071
AN - SCOPUS:84877336712
VL - 5
SP - 707
EP - 722
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 5
ER -