Inhibition of protein isoprenylation impairs Rho-regulated early cellular response to genotoxic stress

Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-kappaB (NF -kappaB) are early cellular responses to genotoxic stress involved in the r egulation of gene expression. Pretreatment of cells with the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin blocked stimulation of JNK1 act ivity by UV irradiation and by treatment with the alkylating compound methy l methanesulfonate but did not affect activation of extracellular signal-re gulated kinase 2 by UV light. Lovastatin also attenuated UV-induced degrada tion of the NF-kappaB inhibitor I kappaB alpha. The effects of lovastatin o n UV-triggered stimulation of JNK1 as well as on I kappaB alpha degradation were reverted by cotreatment with geranylgeranylpyrophosphate but not with farnesylpyrophosphate. Both a geranylgeranyltransferase type I inhibitor a nd a farnesyltransferase inhibitor blocked JNK1 stimulation by UV irradiati on 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 inhibi ted by lovastatin. In line with this hypothesis, Rho-inactivating toxin B f rom Clostridium difficile abolished both JNK1 activation and I kappaB alpha degradation evoked by UV irradiation. In summary, lovastatin-mediated inhi bition of protein isoprenylation abrogates cellular stress responses involv ing JNK- and NF-kappaB-regulated pathways, which seems to be caused by inac tivation of Rho GTPases.