Metallothionein-III provides neuronal protection through activation of nuclear factor-kappaB via the TrkA/phosphatidylinositol-3 kinase/Akt signaling pathway.
Metallothionein (MT)-III is associated with resistance to neuronal injury. However, the underlying mechanism for its effects is unclear. The present study investigated the mechanisms of MT-III protection of neuronal cells from hypoxia or DNA damage-induced cell death. MT-III reduced the hydrogen peroxide- or DNA damage-induced effects on neuronal cells, including the cell death, the activation of caspase-3 and -9, and the release of mitochondrial cytochrome c to the cytoplasm in a dose-dependent manner. MT-III also increased the activation of Akt, the phosphorylation and degradation of IkappaB, the nuclear translocation/accumulation and the transcriptional activity of nuclear factor-kappaB (NF-kappaB) in neuronal cells in a dose-dependent manner. The MT-III-induced antiapoptotic effects and increase in NF-kappaB activity were blocked by specific inhibitors of TrkA, phosphatidylinositol-3 kinase (PI3K), Akt, or NF-kappaB, indicating that MT-III provides neuronal protection by activating NF-kappaB through the TrkA/PI3K/Akt signaling pathway.
Kim
Hyung Gyun
HG
Department of Pharmacy and Research Center for Proteineous Materials, College of Pharmacy, Chosun University, Gwangju, South Korea.
Hwang
Yong Pil
YP
Han
Eun Hee
EH
Choi
Chul Yung
CY
Yeo
Chang-Yeol
CY
Kim
Jin Young
JY
Lee
Kwang Youl
KY
Jeong
Hye Gwang
HG
D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D000090023:Metallothionein 3; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D053148:Caspase 3; D053453:Caspase 9; D045304:Cytochromes c; D000090023:Metallothionein 3; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020917:Receptor, trkA