Abstract
Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result. Furthermore, the potential effect MeHg might have on the non-receptor tyrosine kinase, Fyn, has not been addressed. Fyn phosphorylates Nrf2 in the nucleus, resulting in its inactivation, and consequent downregulation of the oxidative stress response. Here, we observe Nrf2 translocates to the nucleus subsequent to MeHg-induced oxidative stress. This response is concomitant with reduced Fyn expression and nuclear localization. Moreover, we detected an increase in phosphorylated Akt and glycogen synthase kinase 3 beta (GSK-3β) at activating and inhibitory sites, respectively. Akt phosphorylates and inhibits GSK-3β, which subsequently prevents Fyn phosphorylation to signal nuclear import. Our results demonstrate MeHg downregulates Fyn to maintain Nrf2 activity, and further illuminate a potential mechanism by which MeHg elicits neurotoxicity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 200-206 |
| Number of pages | 7 |
| Journal | NeuroToxicology |
| Volume | 62 |
| DOIs | |
| State | Published - Sep 1 2017 |
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Keywords
- Fyn
- Methylmercury
- Nrf2
- Oxidative stress
ASJC Scopus subject areas
- Neuroscience(all)
- Toxicology
Cite this
Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn. / Culbreth, Megan; Zhang, Ziyan; Aschner, Michael.
In: NeuroToxicology, Vol. 62, 01.09.2017, p. 200-206.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn
AU - Culbreth, Megan
AU - Zhang, Ziyan
AU - Aschner, Michael
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result. Furthermore, the potential effect MeHg might have on the non-receptor tyrosine kinase, Fyn, has not been addressed. Fyn phosphorylates Nrf2 in the nucleus, resulting in its inactivation, and consequent downregulation of the oxidative stress response. Here, we observe Nrf2 translocates to the nucleus subsequent to MeHg-induced oxidative stress. This response is concomitant with reduced Fyn expression and nuclear localization. Moreover, we detected an increase in phosphorylated Akt and glycogen synthase kinase 3 beta (GSK-3β) at activating and inhibitory sites, respectively. Akt phosphorylates and inhibits GSK-3β, which subsequently prevents Fyn phosphorylation to signal nuclear import. Our results demonstrate MeHg downregulates Fyn to maintain Nrf2 activity, and further illuminate a potential mechanism by which MeHg elicits neurotoxicity.
AB - Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result. Furthermore, the potential effect MeHg might have on the non-receptor tyrosine kinase, Fyn, has not been addressed. Fyn phosphorylates Nrf2 in the nucleus, resulting in its inactivation, and consequent downregulation of the oxidative stress response. Here, we observe Nrf2 translocates to the nucleus subsequent to MeHg-induced oxidative stress. This response is concomitant with reduced Fyn expression and nuclear localization. Moreover, we detected an increase in phosphorylated Akt and glycogen synthase kinase 3 beta (GSK-3β) at activating and inhibitory sites, respectively. Akt phosphorylates and inhibits GSK-3β, which subsequently prevents Fyn phosphorylation to signal nuclear import. Our results demonstrate MeHg downregulates Fyn to maintain Nrf2 activity, and further illuminate a potential mechanism by which MeHg elicits neurotoxicity.
KW - Fyn
KW - Methylmercury
KW - Nrf2
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85025613585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025613585&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2017.07.028
DO - 10.1016/j.neuro.2017.07.028
M3 - Article
C2 - 28736149
AN - SCOPUS:85025613585
VL - 62
SP - 200
EP - 206
JO - NeuroToxicology
JF - NeuroToxicology
SN - 0161-813X
ER -