title: Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells.
abstract: Benzodiazepine (BZA)-5B, a CAAX farnesyl-transferase inhibitor, was previously shown to block the farnesylation of H-Ras and to reverse the transformed morphology of Rat1 cells expressing oncogenic H-RasV12. Non-transformed Rat1 cells were not affected by BZA-5B, suggesting that they produce a form of Ras whose prenylation is not blocked by this compound. The likely candidate is K-RasB, which differs from H-Ras primarily in the terminal 24 amino acids. In the current study we examined the effect of BZA-5B on the prenylation of a chimeric oncogenic Ras protein designated H/K-RasBV12, consisting of the first 164 amino acids of H-RasV12 followed by the last 24 amino acids of K-RasB. BZA-5B failed to block the prenylation of this chimera and was thus unable to reverse the transformed morphology of Rat1 cells in which it was expressed. Another potent inhibitor of H-Ras farnesylation, L-739,749, also failed to block prenylation of H/K-RasBV12. Similar results were obtained in transfected cells expressing a widely used version of K-RasBV12 containing a 10-amino acid extension at its NH2 terminus. Neither BZA-5B nor L-739,749 reversed the transformed morphology of cells expressing H/K-RasBV12. The resistance of K-RasB to farnesyltransferase inhibition provides a likely explanation for the resistance of nontransformed cells to the growth inhibitory effects of BZA-5B and L-739,749.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046, USA.
authors.forename: G
authors.initials: G
authors.lastname: James
authors.forename: J L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D008798:Mevalonic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D017368:Protein Prenylation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014166:Transferases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C090156:BZA 5B; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D001569:Benzodiazepines; C087363:L 739749; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D008798:Mevalonic Acid