Javier GIRARDINI

Immuno Oncology Laboratory – Institute of Clinical and Experimental Immunology, IDICER, CONICET-UNR, Rosario, ARGENTINA

Regulation of post-prenylation processing by the p53 pathway: ICMT at the center of therapeutic strategies in cancer

Host: G. Del Sal

Mutations in the p53 gene are among the most frequent alterations in human cancer. Our group is interested in identifying mechanisms of tumor aggressiveness associated to alter- ations in the p53 pathway. Through analysis of gene expression profiles we identified genes related to cell metabolism that are regulated by p53 family members. In particular, we found that wt and tumor-associated p53 point mutants differentially regulate the expression of ICMT (Isoprenylcysteine Carboxymethyl Transferase), suggesting that alterations on the p53 pathway enhance ICMT expression during tumor progression. ICMT catalyzes the last step in the Prenylation Pathway, consisting in the methylation of the C-terminus on prenylated proteins. This modification, regulates critical functional aspects of substrate proteins in- volved in oncogenic mechanisms, including several members of the Ras and Rho GTPases families. We studied the effect of ICMT on aggressive phenotypes in vitro and metastasis development in vivo. Our results support the notion that increased ICMT levels promote
the development of aggressive tumors, and underline its relevance as a therapeutic target. With the aim of finding novel ICMT inhibitors with pharmacological potential we generated molecules derived from thiosalicylic acid and characterized their antiproliferative activity.

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