Molecular basis of tumor aggressiveness: In vivo analysis of signalling pathways altered by Pin1

IBARRA SOLANGE; BORINI CARLA; GIRARDINI J.E.

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2012

Genetic and epigenetic alterations conspire to wire aberrant signaling circuits that modify cell behavior, propelling the acquisition of aggressive tumor phenotypes. Previously, we identified Pin1 as a critical link between oncogenic signaling and downstream mechanisms of tumor aggressiveness. Pin1 modulates the function of protein substrates through conformational changes induced by isomerization of peptide bonds in phosphorylated S-P or T-P motifs. The ability to link protein function with prolil-directed phosphorylation allows Pin1 to act as a global modulator of biological responses. However, the actual consequences of Pin1 overexpression in cancer are difficult to asses in vivo, due to the variety of substrates and the complex array of phosphorylation signals active in individual cell types. In an attempt to characterize alterations elicited by Pin1 in vivo we are modeling Pin1 overexpression in zebrafish embryogenesis, which provides a unique model to study pathways that govern development but also cooperate with oncogenic mechanisms in tumor cells. We have isolated a sequence coding for zebrafish Pin1 and analyzed gene expression during early development. Transient overexpression of Pin1 through microinjection of 1-cell embryos showed that forebrain is altered, suggesting that cell types involved in the development of this area are particularly sensible to Pin1 deregulation.