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Vol. 283, Issue 2, 901-909, 1997
Institut für Pharmakologie und Toxikologie, Universität
Freiburg, D-79104 Freiburg, Germany
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.
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