Activation of activator protein-1 DNA binding activity due to low level manganese exposure in pheochromocytoma cells

Abstract

Low-level exposure of manganese (Mn 2+) induces adverse neurological effects. We have previously shown that low-level Mn 2+ exposure induces cell death in dopaminergic neurons, in which the redox-sensitive transcription factor nuclear factor kappa-B (NF-κB) 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 Mn 2+ (0–10 μM) 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 Mn 2+ exposure. In addition, Mn 2+ 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-κB 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 Mn 2+ exposure in the present study may have a significant cytotoxic effect on neuronal function.