Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner.

Abstract

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.

• Authors: Yong Pil Hwang, Hyung Gyun Kim, Eun Hee Han, Hye Gwang Jeong
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 231 Issue 3 Pg. 318-27 (Sep 15 2008) ISSN: 1096-0333 [Electronic] United States
• PMID: 18554677 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Metallothionein 3
• NF-E2-Related Factor 2
• Nerve Tissue Proteins
• Reactive Oxygen Species
• Oxidopamine
• Heme Oxygenase-1
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Active Transport, Cell Nucleus (physiology)
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Heme Oxygenase-1 (biosynthesis, genetics)
• Humans
• Metallothionein 3
• NF-E2-Related Factor 2 (genetics, metabolism, physiology)
• Nerve Tissue Proteins (physiology)
• Oxidative Stress (drug effects, physiology)
• Oxidopamine (antagonists & inhibitors)
• Phosphatidylinositol 3-Kinases (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)