epidermal-growth-factor and farnesyl-pyrophosphate

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Antineoplastic Agents; Benzamides; Benzodiazepines; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Endothelial Growth Factors; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Erlotinib Hydrochloride; Farnesyltranstransferase; Gefitinib; Humans; Imatinib Mesylate; Imidazoles; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Lymphokines; Metalloendopeptidases; Multicenter Studies as Topic; Piperazines; Polyisoprenyl Phosphates; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Quinolones; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Intermediary metabolites of cholesterol synthetic pathway are involved in cell proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks mevalonate synthesis, and has been shown to inhibit mesangial cell proliferation associated with diverse glomerular diseases. Since inhibition of farnesylation and plasma membrane anchorage of the Ras proteins is one suggested mechanism by which lovastatin prevents cellular proliferation, we investigated the effect of lovastatin and key mevalonate metabolites on the activation of mitogen-activated protein kinase (MAP kinase) and Ras in murine glomerular mesangial cells. The preincubation of mesangial cells with lovastatin inhibited the activation of MAP kinase stimulated by either FBS, PDGF, or EGF. Mevalonic acid and farnesyl-pyrophosphate, but not cholesterol or LDL, significantly prevented lovastatin-induced inhibition of agonist-stimulated MAP kinase. Lovastatin inhibited agonist-induced activation of Ras, and mevalonic acid and farnesylpyrophosphate antagonized this effect. Parallel to the MAP kinase and Ras data, lovastatin suppressed cell growth stimulated by serum, and mevalonic acid and farnesylpyrophosphate prevented lovastatin-mediated inhibition of cellular growth. These results suggest that lovastatin, by inhibiting the synthesis of farnesol, a key isoprenoid metabolite of mevalonate, modulates Ras-mediated cell signaling events associated with mesangial cell proliferation.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cell Division; Cell Line; Cells, Cultured; Cholesterol; Enzyme Activation; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Glomerular Mesangium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; MAP Kinase Kinase Kinases; Mevalonic Acid; Mice; Mitogen-Activated Protein Kinase Kinases; Platelet-Derived Growth Factor; Polyisoprenyl Phosphates; Protein Kinase Inhibitors; Protein Kinases; Sesquiterpenes; Signal Transduction