Abstract

Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-κB (NF-κB) 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-κB inhibitor IκBα. The effects of lovastatin on UV-triggered stimulation of JNK1 as well as on IκBα 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-κB. This indicates that different types of isoprenylated proteins impair UV-induced signaling to JNK1 and NF-κB, 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 fromClostridium difficile abolished both JNK1 activation and IκBα degradation evoked by UV irradiation. In summary, lovastatin-mediated inhibition of protein isoprenylation abrogates cellular stress responses involving JNK- and NF-κB-regulated pathways, which seems to be caused by inactivation of Rho GTPases.