Activation of activator protein-1 DNA binding activity due to low level manganese exposure in pheochromocytoma cells.
Low-level exposure of manganese (Mn2+) induces adverse neurological effects. We have previously shown that low-level Mn2+ exposure induces cell death in dopaminergic neurons, in which the redox-sensitive transcription factor nuclear factor kappa-B (NF-kappaB) and associated mitogen-activated protein kinase (MAPK) were stimulated. In continuation of this work, we evaluated the activator protein-1 (AP-1). DNA binding activity and N-terminal c-Jun kinase (JNK) activation due to low-level exposure to manganese. Rat catecholaminergic-rich pheochromocytoma (PC12) cells were exposed to low concentrations of Mn2+ (0-10 microM) for 120 min and examined changes in AP-1 DNA binding activity by electrophoretic mobility shift assay (EMSA). Mn(2+)-exposed cells produced a eightfold increase in AP-1 DNA binding activity compared to untreated controls. This significant increase was seen within 60 min after Mn2+ exposure. In addition, Mn2+ activated N-terminal c-Jun kinase, suggesting that the JNK pathway is involved in Mn(2+)-induced AP-1 activation. Thus, JNK activation may in turn stimulate AP-1 via c-Jun phosphorylation. Since the transcription factors NF-kappaB and AP-1 have been shown to play an essential role in oxidative stress related toxicity, we suggest that induction of the signaling factor AP-1 during Mn2+ exposure in the present study may have a significant cytotoxic effect on neuronal function.
Wise
Kimberly
K
Molecular Neurotoxicology Laboratory, Department of Biology, Texas Southern University, Houston, TX-77004, USA.
Manna
Sunil
S
Barr
Johnny
J
Gunasekar
Palur
P
Ramesh
Govindarajan
G
D000818:Animals; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases; D008345:Manganese / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D004273:DNA, Neoplasm; D018808:Transcription Factor AP-1; D008345:Manganese; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases