Inhibition of Protein Isoprenylation Impairs Rho-Regulated Early Cellular Response to Genotoxic Stress
- 1Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Mainz, Germany (R.G., B.K., G.F.); and 2Institute of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany (K.A.)
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.
Footnotes
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Send reprint requests to: Gerhard Fritz, Division of Applied Toxicology, Institute of Toxicology, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. E-mail: fritz{at}mail.uni-mainz.de
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This work was supported by the Deutsche Forschungsgemeinschaft (Grant Fr-1241/1–3).
- Abbreviations:
- Rho
- Ras-homologous
- MAP
- mitogen-activated protein
- ERK
- extracellular signal-regulated kinase
- JNK
- c-Jun N-terminal kinase
- NF-κB
- nuclear factor κB
- TNFα
- tumor necrosis factor α
- IκBα
- inhibitor κBα
- HMG
- hydroxymethyl glutaryl
- FTI
- farnesyltransferase inhibitor
- GGTI
- geranylgeranyltransferase type I inhibitor
- FCS
- fetal calf serum
- CHO
- Chinese hamster ovary
- AP-1
- activator protein 1
- MMS
- methyl methanesulfonate
- FPP
- farnesylpyrophosphate
- GGPP
- geranylgeranylpyrophosphate
- LT
- lethal toxin from C. sordellii
- ToxB
- toxin B from C. difficile
- GGTase
- geranylgeranyltransferase
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- Received March 17, 2000.
- Accepted September 7, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
