A Farnesyl-Protein Transferase Inhibitor Induces p21 Expression and G1 Block in p53 Wild Type Tumor Cells

摘要: Farnesylation is required for the membrane partition and function of several proteins, including Ras. Farnesyl-protein transferase inhibitors (FTIs) were developed to prevent Ras processing thus be effective agents treatment cancers harboring mutated ras. However, FTIs inhibit growth most tumor cells xenograft models, irrespective whether they possess Furthermore, antiproliferative effect not correlated with inhibition Ki-Ras processing; tumors wild type rasare inhibited, are particularly toxic. These data suggest that mechanism FTI action complex may involve other targets besides To begin understand how work, we investigated inhibition. causes G1 arrest in a subset sensitive lines. This accomplished by transcriptional induction p21, which mediates cyclin E-associated protein kinase activity, pRb hypophosphorylation DNA replication. Induction p21 p53-dependent; it does occur mutant p53 or expressing human papillomavirus E6. neither nor cell proliferation. still blocks deficient these proteins. In absence block relaxed, replication affected, become polyploid undergo apoptosis. results farnesylated protein(s) involved regulating coordinating entrance into S, consequences mutations found cell.