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

Abstract

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-ischemia (HI); however, how NP1 is induced in hypoxic-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 (-/-) null primary cortical neurons. Declines in phospho-Akt (i.e. deactivation) were observed concurrent with decreased phosphorylation of its downstream substrate GSK-3α/β (at Ser21/Ser9) (i.e. activation) and increased GSK-3α 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-3α/β and subsequently enhanced NP1 induction. Whereas, overexpression of constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) increased GSK-α/β phosphorylation and attenuated NP1 induction. Transfection of neurons with GSK-3α 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-3α- and GSK-3β-dependent mechanism of NP1 induction and point to a novel mechanism in the regulation of hypoxic-ischemic neuronal death.

• Authors: Juliet C Russell, Koji Kishimoto, Cliona O'Driscoll, Mir Ahamed Hossain
• Journal: Cellular signalling (Cell Signal) Vol. 23 Issue 4 Pg. 673-82 (Apr 2011) ISSN: 1873-3913 [Electronic] England
• PMID: 21130869 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Nerve Tissue Proteins
• neuronal pentraxin
• C-Reactive Protein
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Animals
• C-Reactive Protein (genetics, metabolism)
• Cell Culture Techniques
• Cell Death
• Cell Hypoxia
• Cell Survival
• Cells, Cultured
• Enzyme Activation
• Gene Knockdown Techniques
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hypoxia-Ischemia, Brain (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Rats
• Rats, Inbred F344