IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
PIN1 PROMOTES THE ACQUISITION OF AN AGGRESSIVE PHENOTYPE BY ENHANCING MUTANT P53 GAIN OF FUNCTION
Autor/es:
GIRARDINI J.E.; NAPOLI M.; MAROTTA C.; DEL SAL G.
Lugar:
Akko, Israel
Reunión:
Workshop; 4th International Workshop on Mutant p53; 2009
Resumen:
P53 is frequently mutated in tumor tissues and the majority of these mutations are missense, thus leading to the expression of full-length mutant proteins. Several lines of evidence have established that a subset of these p53 mutants gain new oncogenic functions and concur to the development of invasive and metastatic phenotypes (gain of function, GOF). However in spite of having been the object of extensive studies, mutant p53 still retains several aspects that need to be unveiled. We have shown that the prolyl isomerase Pin1 is able to interact with p53 point mutants, indicating that Pin1 may regulate mutant p53 GOF. Deregulated action of Pin1 can cooperate with tumorigenesis by amplifying signaling through several oncogenic pathways. Remarkably, we and others have shown that Pin1 is over-expressed in breast cancers (Rustighi et al 2009). In order to determine if there is a functional interaction between Pin1 and mutant p53 we used a model system of oncogene-induced transformation in primary mouse fibroblasts. We found that mutant p53 cooperates with oncogenic Ras in cell transformation and that Pin1 is necessary for this cooperation. Moreover, lack of Pin1 impairs the ability of mutant p53 to enhance the proliferation of tumor xenografts in nude mice. Mutant p53 GOF was associated with the development of metastasis in mouse models, therefore, we analyzed the involvement of mutant p53 in cell migration, since the ability to migrate is essential for tumor cells to develop metastasis. This is a critical aspect in the progression of the disease since metastasis remains the cause of death in 90% of patients with solid tumors. We observed that mutant p53 as well as Pin1 are necessary for cell migration in vitro. Moreover, our results suggest that Pin1 may regulate cell migration by enhancing the interaction between mutant p53 and p63. Previous work from our laboratory unveiled a key role for Pin1, acting in a phosphorylation-dependent manner, to produce conformational changes required for the full transcriptional activation of both wt p53 and p73 (Zacchi et al. 2002 Mantovani et al. 2004, Mantovani et al. 2007). Therefore, our results are consistent with the idea that Pin1, under physiological conditions, may act as a fine tuner of the tumor suppressor function of wt p53, however, during the transformation process, it can change its role becoming a dangerous amplifier of mutant p53 oncogenic activity.