Rho GTPases are involved in the regulation of NF-kappa B by genotoxic stress

A common cellular response to genotoxic agents and inflammatory cytokines i s the activation of NF-kappaB. Here, we addressed the question of whether s mall GTPases of the Rho family are involved in the stimulation of NF-kappaB signaling by genotoxic agents or TNF alpha in HeLa cells. Inhibition of is oprenylation of Rho proteins by use of the HMG-CoA reductase inhibitor lova statin attenuated UV-, doxorubicin-, and TNF alpha -induced degradation of I kappaB alpha as well as drug-stimulated DNA binding activity of NF-kappaB , Furthermore, NF-kappaB-regulated gene expression stimulated by either UV irradiation or treatment with TNF alpha was abrogated by lovastatin pretrea tment. This indicates that isoprenylated regulatory proteins participate in the regulation of NF-kappaB by DNA-damaging agents as well as by TNF alpha . Specific blockage of Rho signaling by Clostridium difficile toxin B atten uated UV- and doxorubicin-induced activation of NF-kappaB, but did not affe ct stimulation of NF-kappaB by TNF alpha. Obviously, signaling to NF-kappaB by genotoxic and nongenotoxic stimuli occurs via different molecular mecha nisms, either involving Rho GTPases or not. Based on the data, we suggest R ho GTPases to be essentially required for genotoxic stress-induced signalin g to NF-kappaB. (C) 2001 Academic Press.