Protein kinase C protects from DNA damage-induced necrotic cell death by inhibiting poly(ADP-ribose) polymerase-1.
The goal of the current study, conducted in freshly isolated thymocytes was (1) to investigate the possibility that the activation of poly(ADP-ribose) polymerase-1 (PARP-1) in an intact cell can be regulated by protein kinase C (PKC) mediated phosphorylation and (2) to examine the consequence of this regulatory mechanism in the context of cell death induced by the genotoxic agent. In cells stimulated by the PKC activating phorbol esters, DNA breakage was unaffected, PARP-1 was phosphorylated, 1-methyl-3-nitro-1-nitrosoguanidine-induced PARP activation and cell necrosis were suppressed, with all these effects attenuated by the PKC inhibitors GF109203X or Gö6976. Inhibition of cellular PARP activity by PKC-mediated phosphorylation may provide a plausible mechanism for the previously observed cytoprotective effects of PKC activators.
Hegedus
Csaba
C
Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, H-4012 Debrecen, Nagyerdei krt. 98, Hungary.
Lakatos
Petra
P
Oláh
Gábor
G
Tóth
Balázs I
BI
Gergely
Szabolcs
S
Szabó
Eva
E
Bíró
Tamás
T
Szabó
Csaba
C
Virág
László
L
D000818:Animals; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology; D019610:Cytoprotection; D004249:DNA Damage; D004789:Enzyme Activation; D007211:Indoles / Q000493:pharmacokinetics; D008301:Maleimides / Q000493:pharmacokinetics; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D009336:Necrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology
D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D008769:Methylnitronitrosoguanidine; C081021:Go 6976; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; C070515:bisindolylmaleimide I