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Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke

CDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation...

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Autores principales: Tuo, Qing-Zhang, Liuyang, Zhen-Yu, Lei, Peng, Yan, Xiong, Shentu, Yang-Ping, Liang, Jia-Wei, Zhou, Huan, Pei, Lei, Xiong, Yan, Hou, Tong-Yao, Zhou, Xin-Wen, Wang, Qun, Wang, Jian-Zhi, Wang, Xiao-Chuan, Liu, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115431/
https://www.ncbi.nlm.nih.gov/pubmed/30158515
http://dx.doi.org/10.1038/s41419-018-0929-7
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author Tuo, Qing-Zhang
Liuyang, Zhen-Yu
Lei, Peng
Yan, Xiong
Shentu, Yang-Ping
Liang, Jia-Wei
Zhou, Huan
Pei, Lei
Xiong, Yan
Hou, Tong-Yao
Zhou, Xin-Wen
Wang, Qun
Wang, Jian-Zhi
Wang, Xiao-Chuan
Liu, Rong
author_facet Tuo, Qing-Zhang
Liuyang, Zhen-Yu
Lei, Peng
Yan, Xiong
Shentu, Yang-Ping
Liang, Jia-Wei
Zhou, Huan
Pei, Lei
Xiong, Yan
Hou, Tong-Yao
Zhou, Xin-Wen
Wang, Qun
Wang, Jian-Zhi
Wang, Xiao-Chuan
Liu, Rong
author_sort Tuo, Qing-Zhang
collection PubMed
description CDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation were observed in the hippocampus of the rats that had been subjected to middle cerebral artery occlusion, both of which were reversed by pretreatment with zinc chelator; while p35 cleavage and calpain activation in ischemia were not reversed. Zinc incubation resulted in CDK5-Tyr15 phosphorylation and CDK5 activation, without increasing p35 cleavage in cultured cells. Site mutation experiment confirmed that zinc-induced CDK5 activation was dependent on Tyr15 phosphorylation. Further exploration showed that Src kinase contributed to zinc-induced Tyr15 phosphorylation and CDK5 activation. Src kinase inhibition or expression of an unphosphorylable mutant Y15F-CDK5 abolished Tyr15 phosphorylation, prevented CDK5 activation and protected hippocampal neurons from ischemic insult in rats. We conclude that zinc-induced CDK5-Tyr15 phosphorylation underlies CDK5 activation and promotes ischemic neuronal death in stroke.
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spelling pubmed-61154312018-08-30 Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke Tuo, Qing-Zhang Liuyang, Zhen-Yu Lei, Peng Yan, Xiong Shentu, Yang-Ping Liang, Jia-Wei Zhou, Huan Pei, Lei Xiong, Yan Hou, Tong-Yao Zhou, Xin-Wen Wang, Qun Wang, Jian-Zhi Wang, Xiao-Chuan Liu, Rong Cell Death Dis Article CDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation were observed in the hippocampus of the rats that had been subjected to middle cerebral artery occlusion, both of which were reversed by pretreatment with zinc chelator; while p35 cleavage and calpain activation in ischemia were not reversed. Zinc incubation resulted in CDK5-Tyr15 phosphorylation and CDK5 activation, without increasing p35 cleavage in cultured cells. Site mutation experiment confirmed that zinc-induced CDK5 activation was dependent on Tyr15 phosphorylation. Further exploration showed that Src kinase contributed to zinc-induced Tyr15 phosphorylation and CDK5 activation. Src kinase inhibition or expression of an unphosphorylable mutant Y15F-CDK5 abolished Tyr15 phosphorylation, prevented CDK5 activation and protected hippocampal neurons from ischemic insult in rats. We conclude that zinc-induced CDK5-Tyr15 phosphorylation underlies CDK5 activation and promotes ischemic neuronal death in stroke. Nature Publishing Group UK 2018-08-29 /pmc/articles/PMC6115431/ /pubmed/30158515 http://dx.doi.org/10.1038/s41419-018-0929-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tuo, Qing-Zhang
Liuyang, Zhen-Yu
Lei, Peng
Yan, Xiong
Shentu, Yang-Ping
Liang, Jia-Wei
Zhou, Huan
Pei, Lei
Xiong, Yan
Hou, Tong-Yao
Zhou, Xin-Wen
Wang, Qun
Wang, Jian-Zhi
Wang, Xiao-Chuan
Liu, Rong
Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title_full Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title_fullStr Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title_full_unstemmed Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title_short Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
title_sort zinc induces cdk5 activation and neuronal death through cdk5-tyr15 phosphorylation in ischemic stroke
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115431/
https://www.ncbi.nlm.nih.gov/pubmed/30158515
http://dx.doi.org/10.1038/s41419-018-0929-7
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