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

Boglarka Racz, Katalin Hanto, Antal Tapodi, Izabella Solti, Nikoletta Kalman, Peter Jakus, Krisztina Kovacs, Balazs Debreceni, Ferenc Gallyas, Balazs Sumegi

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 JNK 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.

Original languageEnglish
Pages (from-to)1978-1988
Number of pages11
JournalFree Radical Biology and Medicine
Volume49
Issue number12
DOIs
Publication statusPublished - Dec 15 2010

    Fingerprint

Keywords

  • Apoptosis
  • Free radicals
  • JNK p38
  • MKP-1 expression
  • PARP-1 inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this