ICMT cooperates with tumor aggressiveness and it is under complex control by p53

BORINI ETICHETTI, CARLA M.; DI BENEDETTO CAROLINA; BAGLIONI, MARÍA VIRGINIA; BICCIATO, SILVIO; MENACHO MÁRQUEZ, MAURICIO; GIRARDINI, JAVIER E.

Congreso; Reunión anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2018

ICMT plays a key role in the regulation of prenylated proteins by catalysing carboxymethylation of the C-terminus. Despite growing evidences suggesting that alterations in the prenylated protein network may affect tumor progression, the regulation of this complex post-translational modification process and the specific role of ICMT are not completely understood. Our work unveils a link between post-prenylation processing and the p53 pathway. We found that p53 family members affect ICMT levels. By performing qPCR, luciferase assays, chromatin immunoprecipitation and western blot we characterized the effect of different p53 family members on ICMT expression. Our results suggest that ICMT is under precise regulation in normal cells but becomes overexpressed during tumor progression. We also showed that ICMT overexpression contributes affects tumor-associated phenotypes in vitro and tumor formation in vivo. To gain insight into the molecular mechanisms of these effects we studied the consequences of ICMT deregulation on RAS/MAPK pathway and actin cytoskeleton. Moreover, we found a correlation between p53 status and ICMT expression in breast and lung cancer patients. We also analysed the impact of ICMT overexpression on clinical outcome and defined groups with differential behaviour, conditioned by p53 status. Our results suggest that the functional interplay between p53 family members and p53 mutant forms will affect ICMT levels during tumorigenesis and this, in turn, will cooperate to drive mechanisms of tumor aggressiveness.