title: Inhibition of protein isoprenylation impairs rho-regulated early cellular response to genotoxic stress.
abstract: Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-kappaB (NF-kappaB) are early cellular responses to genotoxic stress involved in the regulation of gene expression. Pretreatment of cells with the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin blocked stimulation of JNK1 activity by UV irradiation and by treatment with the alkylating compound methyl methanesulfonate but did not affect activation of extracellular signal-regulated kinase 2 by UV light. Lovastatin also attenuated UV-induced degradation of the NF-kappaB inhibitor IkappaBalpha. The effects of lovastatin on UV-triggered stimulation of JNK1 as well as on IkappaBalpha degradation were reverted by cotreatment with geranylgeranylpyrophosphate but not with farnesylpyrophosphate. Both a geranylgeranyltransferase type I inhibitor and a farnesyltransferase inhibitor blocked JNK1 stimulation by UV irradiation without impairing signaling to NF-kappaB. This indicates that different types of isoprenylated proteins impair UV-induced signaling to JNK1 and NF-kappaB, respectively. Since lovastatin caused a rapid decrease in the level of membrane-bound Rho GTPases, we hypothesize that Rho signaling is inhibited by lovastatin. In line with this hypothesis, Rho-inactivating toxin B from Clostridium difficile abolished both JNK1 activation and IkappaBalpha degradation evoked by UV irradiation. In summary, lovastatin-mediated inhibition of protein isoprenylation abrogates cellular stress responses involving JNK- and NF-kappaB-regulated pathways, which seems to be caused by inactivation of Rho GTPases.
authors.affiliation: Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Mainz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gnad
authors.forename: K
authors.initials: K
authors.lastname: Aktories
authors.forename: B
authors.initials: B
authors.lastname: Kaina
authors.forename: G
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006367:HeLa Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009152:Mutagenicity Tests; D016328:NF-kappa B / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D008148:Lovastatin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins