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

Cell Death & Disease
Qing-Zhang TuoRong Liu

Abstract

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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Citations

Jan 6, 2021·Cancers·Phuong Anh Do, Chang Hoon Lee
Oct 28, 2020·Journal of Molecular Neuroscience : MN·Qing-Zhang TuoPeng Lei
Dec 17, 2020·Frontiers in Molecular Neuroscience·Alberto GranzottoStefano L Sensi
Jul 28, 2020·Neurotoxicology·Zhuoya XieJianfeng Zhao
Aug 15, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Si-Juan HuangZhao-Ying Liu
Jan 25, 2022·Experimental and Therapeutic Medicine·Yu DingJing Zheng

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Methods Mentioned

BETA
transfect
protein assay
electrophoresis
ELISA
immnunoprecipitation

Software Mentioned

Image J
Pro Plus
SPSS
Imaging

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