Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB.
Protein farnesyltransferase inhibitors (FTIs) inhibit Ras transformation and Ras-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, and cell growth. A significant question that needed to be addressed was whether FTIs could directly alter the prenylation as well as the function of RhoB in cells. This issue is complex because farnesylated and geranylgeranylated forms of RhoB (RhoB-F and RhoB-GG) both exist in cells. 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 with the decrease in RhoB-F. In addition to altering RhoB prenylation, L-739,749 suppressed RhoB-dependent cell growth. Taken together, the results 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 the anti-transforming effects of FTIs and indicate that differently prenylated forms of RhoB may have unique functions.
Lebowitz
P F
PF
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Casey
P J
PJ
Prendergast
G C
GC
Thissen
J A
JA
D019883:Alkyl and Aryl Transferases; D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D017368:Protein Prenylation; D051381:Rats; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020743:rhoB GTP-Binding Protein
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009842:Oligopeptides; C087363:L 739749; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D019204:GTP-Binding Proteins; D020743:rhoB GTP-Binding Protein