FARNESYLTRANSFERASE INHIBITORS ARE INHIBITORS OF RAS BUT NOT R-RAS2 TC21, TRANSFORMATION/

Recent results from several laboratories including ours strongly sugge st that farnesyltransferase (FT) inhibitors belonging to distinct chem ical classes block growth of oncogenic Ras transformed cells at concen trations that do not affect the growth and viability of normal cells, This is despite blocking the farnesylation and thus the membrane assoc iation of Ras in both cell types. This is a paradox given the requirem ent for Ras function in normal cell growth. Recent evidence that R-Ras 2/TC21 utilizes components of Ras signal transduction pathways to trig ger cellular transformation (Graham et al., MCB 14, 4108-4115, 1994) p rompted 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 treat ed with FT inhibitors. In this study, we demonstrated that a cell acti ve bisubstrate analog FT inhibitor, BMS-186511, completely blocked the function of oncogenic Ras, but did not affect the function of oncogen ic R-Ras2/TC21, as determined by several criteria including inhibition of anchorage dependent and independent growth, reversal of transforme d morphology and restoration of actin cytoskeleton. While it is known that TC21 protein becomes prenylated, it is not known whether it is fa rnesylated or geranylgeranylated. Our in vitro prenylation experiments indicate that R-Ras2/TC21 protein serves as a good substrate for FT a s well as geranylgeranyltransferase I (GGTI) and thus provide the appa rent molecular basis for these differences. Overall, these results, co upled with the ubiquitous expression of R-Ras2/TC21 in many cells incl uding untransformed NIH3T3 cells, are consistent with the possibility that R-Ras2/TC21 may be one of the factors that render normal cells in sensitive to the growth inhibitory action of FT inhibitors.