Neuronal pentraxin 1 induction in hypoxic 13;ischemic neuronal death is regulated via a glycogen synthase kinase-3;1;/β dependent mechanism

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• 作者：Juliet C. Russell^a ; Koji Kishimoto^a ; ^b ; Cliona O'Driscoll^a ; ^b ; Mir Ahamed Hossain^a ; ^b ; ^{hossain@kennedykrieger.org}
• 关键词：Neuronal pentraxin 1 ; Hypoxic 13 ; ischemic neuronal injury ; Neonatal brain injury ; Neuroprotection ; Glycogen synthase kinase 3;1 ; /β ; Akt
• 刊名：Cellular Signalling
• 出版年：2011
• 出版时间：April 2011
• 年：2011
• 卷：23
• 期：4
• 页码：673-682
• 全文大小：1225 K

文摘

Intracellular signaling pathways that regulate the production of lethal proteins in central neurons are not fully characterized. Previously, we reported induction of a novel neuronal protein neuronal pentraxin 1 (NP1) in neonatal brain injury following hypoxia 13;ischemia (HI); however, how NP1 is induced in hypoxic 13;ischemic neuronal death remains elusive. Here, we have elucidated the intracellular signaling regulation of NP1 induction in neuronal death. Primary cortical neurons showed a hypoxic-ischemia time-dependent increase in cell death and that NP1 induction preceded the actual neuronal death. NP1 gene silencing by NP1-specific siRNA significantly reduced neuronal death. The specificity of NP1 induction in neuronal death was further confirmed by using NP1 ("12;/"12;) null primary cortical neurons. Declines in phospho-Akt (i.e. deactivation) were observed concurrent with decreased phosphorylation of its downstream substrate GSK-3;1;/β (at Ser21/Ser9) (i.e. activation) and increased GSK-3;1; and GSK-3β kinase activities, which occurred prior to NP1 induction. Expression of a dominant-negative inhibitor of Akt (Akt-kd) blocked phosphorylation of GSK-3;1;/β and subsequently enhanced NP1 induction. Whereas, overexpression of constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) increased GSK-;1;/β phosphorylation and attenuated NP1 induction. Transfection of neurons with GSK-3;1; siRNA completely blocked NP1 induction and cell death. Similarly, overexpression of the GSK-3β inhibitor Frat1 or the kinase mutant GSK-3βKM, but not the wild-type GSK-3βWT, blocked NP1 induction and rescued neurons from death. Our findings clearly implicate both GSK-3;1;- and GSK-3β-dependent mechanism of NP1 induction and point to a novel mechanism in the regulation of hypoxic 13;ischemic neuronal death.