MECHANISMS OF TUMOR AGGRESSIVENESS ACTIVATED BY MUTANT P53

GIRARDINI J.; BORINI CARLA; IBARRA SOLANGE; DI BENEDETTO CAROLINA

Montevideo

Congreso; X ALAMCTA Congress; 2016

Asociación Latinoamericana de mutagénesis, carcinogénesis y teratogénesis ambiental

Cancer is a complex disease originated fromalterations in the mechanisms that regulate cell behavior and tissue homeostasis.It is commonly accepted that such perturbations are the consequence ofaccumulating genetic and epigenetic alterations. The amazing heterogeneity ofalterations found in tumors has obscured our understanding of the etiology ofcancer, making elusive the identification of common mechanisms that may betargeted for clinical therapy. Mutations in the TP53 tumor suppressor gene are among the most common genetic lesionsin human cancers. The TP53 gene ismost frequently hit by missense mutations that lead to the expression of pointmutants. Several of these P53 mutants may acquire new oncogenic functions andconcur to the development of a metastatic phenotype. Despite compellingevidences from mouse models on the pro-metastatic role of p53 mutants, themolecular mechanism underlying this activity remain puzzling. Our work isfocused on the effects of p53 mutants on gene expression and its consequenceson tumour progression. Even if p53 mutants lose the ability to recognizespecific binding sites on target promoters they were shown to affect geneexpression. We identified several target genes whose expression is altered bymutant p53 in breast cancer cells, suggesting in some cases a complex interplaybetween p53 family members. We showed that mutant p53 is activated by anoncogenic circuitry transmitted by proline-directed phosphorylation. A criticalcomponent of this mechanism is the prolil isomerase Pin1, which binds mutantp53 and amplifies its function. The concerted action of Pin1 and mutant p53 leadsto changes in gene expression, inducing a transcriptional program that promotescell migration and invasion. Since Pin1 overexpression is also a frequentalteration in human tumours, we believe that p53 mutation and Pin1overexpression may represent critical events that promote the progression toaggressive tumour phenotypes.