Bv. Bassa et al., Effect of inhibition of cholesterol synthetic pathway on the activation ofRas and MAP kinase in mesangial cells, BBA-MOL CEL, 1449(2), 1999, pp. 137-149
Citations number
51
Categorie Soggetti
Cell & Developmental Biology
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Intermediary metabolites of cholesterol synthetic pathway are involved in c
ell proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl c
oenzyme A reductase, blocks mevalonate synthesis, and has been shown to inh
ibit mesangial cell proliferation associated with diverse glomerular diseas
es. Since inhibition of farnesylation and plasma membrane anchorage of the
Ras proteins is one suggested mechanism by which lovastatin prevents cellul
ar proliferation, we investigated the effect of lovastatin and key mevalona
te metabolites on the activation of mitogen-activated protein kinase (MAP k
inase) and Ras in murine glomerular mesangial cells. The preincubation of m
esangial cells with lovastatin inhibited the activation of MAP kinase stimu
lated by either FBS, PDGF, or EGF. Mevalonic acid and farnesylpyrophosphate
, but not cholesterol or LDL, significantly prevented lovastatin-induced in
hibition of agonist-stimulated MAP kinase. Lovastatin inhibited agonist-ind
uced activation of Ras, and mevalonic acid and farnesylpyrophosphate antago
nized this effect. Parallel to the MAP kinase and Ras data, lovastatin supp
ressed cell growth stimulated by serum, and mevalonic acid and farnesylpyro
phosphate prevented lovastatin-mediated inhibition of cellular growth. Thes
e results suggest that lovastatin, by inhibiting the synthesis of farnesol,
a key isoprenoid metabolite of mevalonate, modulates Ras-mediated cell sig
naling events associated with mesangial cell proliferation. (C) 1999 Elsevi
er Science B.V. All rights reserved.