ggti-297 and Cell-Transformation--Neoplastic

In order to assess the relative contributions of farnesylated and/or geranylgeranylated proteins on cell cycle progression from G1 to S phase we designed potent and selective farnesyltransferase (FTI-277) and geranylgeranyltransferase-I (GGTI-298) inhibitors. Flow cytometry studies showed that treatment of NIH3T3 cells with GGTI-298 or lovastatin, which inhibits both protein farnesylation and geranylgeranylation, arrested cells in G0/G1 whereas cells treated with FTI-277 progressed normally through the cell cycle. [3H]thymidine incorporation studies showed that mevalonate and geranylgeraniol, but not farnesol, released the lovastatin G1 block. Furthermore, mevalonate release of the lovastatin G1 block was inhibited by GGTI-298 but not by FTI-277. These results demonstrate that geranylgeranylated proteins are required for cells to proceed from G1 to S phase, and that farnesylated proteins do not play an essential role in the G1 to S phase transition

Topics: Actins; Alkyl and Aryl Transferases; Animals; Benzamides; Cell Cycle; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Cytoskeleton; Diterpenes; DNA; Enzyme Inhibitors; Farnesol; Fibroblasts; G1 Phase; Genes, ras; GTP-Binding Proteins; Lovastatin; Methionine; Mevalonic Acid; Mice; Protein Prenylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-raf; rap GTP-Binding Proteins; ras Proteins; Resting Phase, Cell Cycle; S Phase; Transferases