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Rupa Latha Maddala, Venkat N. Reddy, P. Vasantha Rao; Lovastatin-Induced Cytoskeletal Reorganization in Lens Epithelial Cells: Role of Rho GTPases. Invest. Ophthalmol. Vis. Sci. 2001;42(11):2610-2615.
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purpose. To understand the involvement of isoprenylated small guanosine
triphosphatases (GTPases) in lovastatin-induced cataractogenesis, Rho-
and Rac-mediated cell adhesion and actin cytoskeletal reorganization
were investigated in lovastatin-treated lens epithelial cells.
methods. The effects of lovastatin on F-actin reorganization (phalloidin
staining), focal adhesion formation (paxillin or vinculin), cell–cell
adhesions (cadherin and β-catenin), and protein tyrosine
phosphorylation were evaluated in human and porcine lens epithelial
cells by immunocytochemical staining with specific antibodies. To
explore the involvement of the Rho and Rac GTPases in
lovastatin-mediated effects, changes in distribution of Rho and Rac
GTPases were analyzed by Western blot analysis, and the effects of
C3-exoenzyme on lovastatin-induced cytoskeletal changes were evaluated
by immunocytochemical analysis.
results. Lovastatin induced drastic changes in cell shape in both human and
porcine lens epithelial cells, including a profound loss of actin
stress fibers, focal adhesions, protein phosphotyrosine, and cell–cell
adhesions. Lovastatin treatment also led to the accumulation of
nonisoprenylated Rho and Rac GTPases in cytosolic fraction.
Supplementation of culture media with geranylgeranyl pyrophosphate
dramatically reversed the lovastatin-induced morphologic and
cytoskeletal changes, whereas farnesyl pyrophosphate was ineffective.
Treatment of cells with C3-exoenzyme (a Rho GTPase-specific inhibitor),
however, abolished the geranylgeranyl-supplementation–induced recovery
from the morphologic and cytoskeletal effects of lovastatin.
conclusions. This study demonstrates that inhibition of protein prenylation by
lovastatin leads to disruption of actin cytoskeletal organization, and
to loss of integrin-mediated focal adhesions and cadherin-mediated
cell–cell adhesions in lens epithelial cells. Based on isoprenoid
supplementation studies, it could be concluded that impairment of
geranylgeranylated Rho and Rac GTPase function is most likely
responsible for lovastatin-induced cytoskeletal changes in lens
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