TY - JOUR T1 - Role of Rho Protein in Lovastatin-Induced Breakdown of Actin Cytoskeleton JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 901 LP - 909 VL - 283 IS - 2 AU - G. Koch AU - C. Benz AU - G. Schmidt AU - C. Olenik AU - K. Aktories Y1 - 1997/11/01 UR - http://jpet.aspetjournals.org/content/283/2/901.abstract N2 - The Rho GTPases are involved in actin cytoskeleton organization and signal transduction. They need polyisoprenylation for membrane association and activation. Lovastatin, a hydroxymethylglutaryl coenzyme A inhibitor, prevents isoprene synthesis and thereby lipid modification of the Rho protein carboxy terminus. Because lovastatin causes rounding up of cultured cells, we investigated whether the compound acts on the actin cytoskeleton through Rho proteins. Lovastatin treatment decreased F-actin content in a time- and concentration-dependent manner. G-actin content remained unchanged. In lovastatin-treated NIH 3T3 cells, the amount of Rho protein which was ADP-ribosylated by Clostridium botulinum exoenzyme C3 decreased in membranes and increased in the cytosol fraction. Cycloheximide prevented lovastatin-induced rounding up of cells. However, after microinjection or direct application of exoenzyme C3, cells treated with cycloheximide and lovastatin rounded up again. On the contrary, lovastatin-treated, round Swiss 3T3 cells reverted to a flat morphology when microinjected with dominant active RhoA (Val14RhoA). Escherichia coli cytotoxic necrotizing factor (CNF1) which activates Rho proteins caused flattening of round, lovastatin-treated NIH 3T3 cells. These results suggest that lovastatin affects the actin cytoskeleton through inactivation of Rho proteins. The American Society for Pharmacology and Experimental Therapeutics ER -