Regulation of MKP-1 expression and MAPK activation by PARP-1 in oxidative stress A new mechanism for the cytoplasmic effect of PARP-1 activation

Previously it was suggested that the release of nuclearly formed ADP-ribose polymers or ADP-ribosylated proteins could be responsible for the cytosolic and mitochondrial effects of poly(ADP-ribose) polymerase (PARP)-1 activation in oxidative stress In this report we provide a novel alternative mechanism We found that reactive oxygen species-activated PARP-1 regulated the activation of JNK and p38 mitogen activated protein kinases (MAPKs) because inhibition of PARP-1 by pharmacons small interfering RNA silencing of PARP-1 expression or the transdominant expression of enzymatically inactive PARP-1 resulted in the inactivation of these MAPKs This regulation was achieved by increased expression and enlarged cytoplasmic localization of MAPK phosphatase 1 (MKP-1) upon PARP-1 inhibition in oxidative stress because changes in MKP-1 expression were reflected in the phosphorylation states of INK and p38 Furthermore we found that in MKP-1-silenced cells PARP inhibition was unable to exert its protective effect indicating the pivotal roles of JNK and p38 in mediating the oxidative-stress-induced cell death as well as that of increased MKP-1 expression in mediating the protective effect of PARP inhibition We suggest that regulation of a protein that can directly influence cytoplasmic signaling cascades at the expression level represents a novel mechanism for the cytoplasmic action of PARP-1 inhibition (C) 2010 Elsevier Inc All rights reserved