Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner.
The zinc-binding protein metallothionein-III (MT-III) is associated with resistance to neuronal injury. However, the underlying mechanism for its effects is unclear. In this study, we demonstrate that MT-III prevents the accumulation of reactive oxygen species (ROS) in dopaminergic SH-SY5Y cells challenged with the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA) by a mechanism that involves phosphatidylinositol 3-kinase (PI3K) and ERK kinase/NF-E2-related factor 2 (Nrf2) dependent induction of the stress response protein heme oxygenase-1 (HO-1). Pretreatment of SH-SY5Y cells with MT-III significantly reduced 6-OHDA-induced generation of ROS, caspase-3 activation, and subsequent cell death. Also, MT-III up-regulates HO-1 expression and this expression confers neuroprotection against oxidative injury induced by 6-OHDA. Moreover, MT-III induces Nrf2 nuclear translocation, which is upstream of MT-III-induced HO-1 expression, and PI3K and ERK1/2 activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. Taken together, these results suggest that the PI3K and ERK/Nrf2 signaling pathway controls the intracellular levels of ROS by regulating the expression of the antioxidant enzyme HO-1.
BK21 Project Team, Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Gwangju, South Korea.
Yong Pil
YP
Hwang
Hyung Gyun
HG
Kim
Eun Hee
EH
Han
Hye Gwang
HG
Jeong
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000090023:Metallothionein 3; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D051547:Heme Oxygenase-1; D000090023:Metallothionein 3; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species