A synthetic superoxide dismutase/catalase mimetic (EUK-134) inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes.
Salen-manganese complexes exhibit powerful superoxide dismutase and catalase activity, with pharmacologic efficacy in several oxidative-stress-associated disease models. Ultraviolet (UV) B not only induces direct DNA damage, but also generates oxidative stress. EUK-134, a salen-manganese complex, might therefore confer a direct protection against UVB-induced oxidative stress and consequently alleviate UVB-damage-induced signal transduction. We investigated the effect of EUK-134 on the UVB-induced accumulation and stabilization of the p53 protein. p53 plays a central role in the UVB response, both as sensor of UVB damage and as a mediator of a protective response. Cells treated with EUK-134 before UVB irradiation showed a significantly lower accumulation of the p53 protein in a concentration-dependent fashion. Furthermore, EUK-134 severely reduced N-terminal phosphorylation of p53. The extracellular signal-regulated kinase ERK and the stress-activated kinases JNK and p38 have been implicated in the UVB-induced N-terminal phosphorylation and accumulation of p53. Pre-treatment with EUK-134 inhibited the UVB-induced activation of these mitogen-activated protein kinase (MAPK) pathways. We hypothesize that EUK-134, by direct protection of the membrane from UVB-induced oxidative damage, reduces oxidative stress induced MAPK signaling and consequently lowers the level of p53 induction. The protection conferred by EUK-134 resulted in a significant increase in cell survival following UVB irradiation.
Department of Dermatology, University of Leuven, Leuven, Belgium.
David
D
Decraene
Katrien
K
Smaers
David
D
Gan
Tom
T
Mammone
Mary
M
Matsui
Daniel
D
Maes
Lieve
L
Declercq
Marjan
M
Garmyn
D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
C433928:EUK-134; D009942:Organometallic Compounds; D012459:Salicylates; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases