FARNESYLTRANSFERASE INHIBITORS ALTER THE PRENYLATION AND GROWTH-STIMULATING FUNCTION OF RHOB

Protein farnesyltransferase inhibitors (FTIs) inhibit Pas transformati on and has-dependent tumor cell growth, but the biological mechanisms underlying these activities is unclear, In previous work, we presented support for the hypothesis that the anti-transforming effects of FTIs depend upon alterations in the function of RhoB, a member of the Rho family of proteins that regulate cytoskeletal actin, cell adhesion, an d cell growth. A significant question that needed to be addressed was whether FTIs could directly alter the prenylation as well as the funct ion of RhoB in cells, This issue is complex because farnesylated and g eranylgeranylated forms of RhoB (RhoB-F and RhoE-GG) both exist in cel ls, Here, we show that RhoB farnesylation in vitro can be catalyzed by protein farnesyltransferase and that the peptidomimetic FTI L-739,749 inhibits the farnesylation of RhoB both in vitro and in intact cells, In drug-treated cells, the level of RhoB-GG increased in parallel wit h the decrease in RhoB-F, In addition to altering RhoB prenylation, L- 739,749 suppressed RhoB-dependent cell growth, Taken together, the res ults suggest that the inhibitory effects of FTIs on RhoB function can be mediated by a relative loss of RhoB-F, a gain of RhoB-GG, or both, Our findings strengthen the causal link between RhoB inhibition and th e anti-transforming effects of FTIs and indicate that differently pren ylated forms of RhoB may have unique functions.