Junior Faculty Lecture: Molecular bases of tumor aggressiveness: mutant p53 and the gateway to altered states

GIRARDINI J.E.

Potrero de los Funes, San Luis

Encuentro; 47º Reunión anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2011

SAIB

Cancer is a complex disease originated from alterations in the mechanisms that regulate cell behavior and tissue homeostasis. It is commonly accepted that such perturbations are the consequence of accumulating genetic and epigenetic alterations. The amazing heterogeneity of alterations found in tumors has obscured our understanding of the etiology of cancer, making elusive the identification of common mechanisms that may be targeted for clinical therapy. Mutations in the TP53 tumor suppressor gene are among the most frequent genetic lesions in human cancers. The TP53 gene is most frequently hit by missense mutations that lead to the expression of point mutants. P53 mutants acquire new oncogenic functions and concur to the development of a metastatic phenotype. We showed that mutant p53 is activated by an oncogenic circuitry transmitted by proline-directed phosphorylation. A critical component of this mechanism is the prolil isomerase Pin1, which binds mutant p53 and amplifies its function. The concerted action of Pin1 and mutant p53 leads to a global alteration of gene expression, inducing a transcriptional program that promotes cell migration and invasion. Since Pin1 overexpression is also a frequent alteration in human tumors, we believe that p53 mutation and Pin1 overexpression may act as molecular switches that promote the progression to aggressive tumor phenotypes.