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

DI BENEDETTO, CAROLINA; MENACHO-MARQUEZ, MAURICIO; BAGLIONI MARIA VIRGINIA; GIRARDINI, JAVIER; BORINI ETICHETTI, CARLA M.; BICCIATO SILVIO

PARANA

Congreso; SAIB (Sociedad Argentina de Investigación en Bioquímica y Biología Molecular); 2018

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