Activation of early signaling transcription factor, NF-κB following low-level manganese exposure

Occupational and environmental exposure to manganese (Mn 2+) is an increasing problem. It manifests neuronal degeneration characterized by dyskinesia resembling Parkinson's disease. The study was performed to test the hypotheses whether exposure to Mn 2+ alters cellular physiology and promotes...

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Veröffentlicht in:Toxicology letters 2002-12, Vol.136 (2), p.151-158
Hauptverfasser: Ramesh, Govindarajan T, Ghosh, Debabrata, Gunasekar, Palur G
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Sprache:eng
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Zusammenfassung:Occupational and environmental exposure to manganese (Mn 2+) is an increasing problem. It manifests neuronal degeneration characterized by dyskinesia resembling Parkinson's disease. The study was performed to test the hypotheses whether exposure to Mn 2+ alters cellular physiology and promotes intracellular signaling mechanism in dopaminergic neuronal cell line. Since transcription factors have been shown to play an essential role in the control of cellular proliferation and survival, catecholaminergic rich pheochromocytoma (PC12) cells were used to measure changes in the DNA binding activities of nuclear factor kappa B (NF-κB) by electrophoretic mobility shift assay (EMSA) following Mn 2+ (0.1–10 μM) exposure. Cells that were exposed to Mn 2+ produced five-fold-activation of transcription factor NF-κB DNA binding activity. This remarkable increase was seen within 30–60 min period of Mn 2+ exposure. Activation of NF-κB DNA binding activity by Mn 2+ at 1.0 μM correlated with proteolytic degradation of the inhibitory subunit IκBα as evidenced in cytosol. Additional experiments on NF-κB reporter gene assay also showed increased NF-κB gene expression at 1.0 and 5.0 μM Mn 2+ and this was completely blocked in the presence of NF-κB translocation inhibitor, IκBα-DN supporting that NF-κB induction occurred during Mn 2+ exposure. In addition, Mn 2+ exposure to PC 12 cells led to activation of signal responsive mitogen activated protein kinase kinase (MAPKK). These results suggest that Mn 2+ at a low dose appears to induce the expression of immediate early gene, NF-κB through MAPKK by a mechanism in which IκBα phosphorylation may be involved.
ISSN:0378-4274
1879-3169
DOI:10.1016/S0378-4274(02)00332-6