Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB.

摘要: Recent results have shown that the ability of farnesyltransferase inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously farnesylated Rho proteins are important targets for alternation by FTIs, based on studies RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss but gain geranylgeranylated (RhoB-GG), which is associated growth-promoting activity. In this study, we tested whether RhoB-GG elicited FTI treatment was sufficient mediate FTI-induced growth inhibition. support hypothesis, when expressed in Ras-transformed cells induced phenotypic reversion, inhibition, activation cycle kinase inhibitor p21WAF1. did not affect phenotype or normal cells. These effects were similar insofar as they all transformed promote anoikis cells, implying response involves loss-of-function effects. Our findings corroborate hypothesis demonstrate gain-of-function part drug mechanism. Gain may explain how human tumor lack mutations. Farnesyltransferase novel class antitumor agents whose development upon discovery posttranslational required oncogenic properties (reviewed references 17, 18, 40, 56). Protein C-terminal addition C15 (farnesyl) C20 (geranylgeranyl) isoprenoids, each them intermediates cholesterol biosynthesis. reactions carried out one three enzymes cell: (FT), geranylgeranyltransferase type I (GGT-I), II (GGT-II; Rab GGT). FT GGT-I related heterodimeric share common subunit. They members subfamilies superfamily small GTPases include CAAX mo