title: Farnesyltransferase inhibitors are inhibitors of Ras but not R-Ras2/TC21, transformation.
abstract: Recent results from several laboratories including ours strongly suggest that farnesyltransferase (FT) inhibitors belonging to distinct chemical classes block growth of oncogenic Ras transformed cells at concentrations that do not affect the growth and viability of normal cells. This is despite blocking the farnesylation and thus the membrane association of Ras in both cell types. This is a paradox given the requirement for Ras function in normal cell growth. Recent evidence that R-Ras2/TC21 utilizes components of Ras signal transduction pathways to trigger cellular transformation (Graham et al., MCB 14, 4108-4115, 1994) prompted us to consider the possibility that R-Ras2/TC21 is involved in some aspects of the growth regulation of normal cells. If so, R-Ras2/TC21 may be compensating for Ras function in untransformed cells treated with FT inhibitors. In this study, we demonstrated that a cell active bisubstrate analog FT inhibitor, BMS-186511, completely blocked the function of oncogenic Ras, but did not affect the function of oncogenic R-Ras2/TC21, as determined by several criteria including inhibition of anchorage dependent and independent growth, reversal of transformed morphology and restoration of actin cytoskeleton. While it is known that TC21 protein becomes prenylated, it is not known whether it is farnesylated or geranylgeranylated. Our in vitro prenylation experiments indicate that R-Ras2/TC21 protein serves as a good substrate for FT as well as geranylgeranyltransferase I (GGTI) and thus provide the apparent molecular basis for these differences. Overall, these results, coupled with the ubiquitous expression of R-Ras2/TC21 in many cells including untransformed NIH3T3 cells, are consistent with the possibility that R-Ras2/TC21 may be one of the factors that render normal cells insensitive to the growth inhibitory action of FT inhibitors.
authors.affiliation: Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Carboni
authors.forename: N
authors.initials: N
authors.lastname: Yan
authors.forename: A D
authors.initials: AD
authors.lastname: Cox
authors.forename: X
authors.initials: X
authors.lastname: Bustelo
authors.forename: S M
authors.initials: SM
authors.lastname: Graham
authors.forename: M J
authors.initials: MJ
authors.lastname: Lynch
authors.forename: R
authors.initials: R
authors.lastname: Weinmann
authors.forename: B R
authors.initials: BR
authors.lastname: Seizinger
authors.forename: C J
authors.initials: CJ
authors.lastname: Der
authors.forename: M
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000473:pathology; D000199:Actins / Q000187:drug effects; D019883:Alkyl and Aryl Transferases; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D051231:Farnesyltranstransferase; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D009842:Oligopeptides / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology*; D015398:Signal Transduction; D013379:Substrate Specificity; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000199:Actins; C093572:BMS 186511; D008565:Membrane Proteins; D009842:Oligopeptides; D010721:Phosphinic Acids; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; C490200:Rras2 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins