title: Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer.
abstract: 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 (p53(MUT) ) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53(MUT) by DNA-PKCS , eventually modulating p53(MUT) stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53(MUT) -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 , p53(MUT) 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.
authors.affiliation: Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Sonego
authors.forename: Monica
authors.initials: M
authors.lastname: Schiappacassi
authors.forename: Sara
authors.initials: S
authors.lastname: Lovisa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dall'Acqua
authors.forename: Marina
authors.initials: M
authors.lastname: Bagnoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.forename: Loredana
authors.initials: L
authors.lastname: Militello
authors.forename: Marco
authors.initials: M
authors.lastname: Napoli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giorda
authors.forename: Barbara
authors.initials: B
authors.lastname: Pivetta
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Barbara
authors.initials: B
authors.lastname: Valeri
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050777:Stathmin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D034741:RNA, Small Interfering; D050777:Stathmin; D016159:Tumor Suppressor Protein p53