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J Cell Sci. 2006 Apr 1;119(Pt 7):1329-40. Epub 2006 Mar 14.

Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death.

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1
System-Biodynamics NCRC, National Research Laboratory of Molecular Neurophysiology and Division of Molecular and Life Science, Pohang University of Science and Technology, Hyoja dong, San31, Pohang, 790-784, South Korea.

Abstract

Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a dual-specificity phosphatase that is involved in the regulation of cell survival, differentiation and apoptosis through inactivating MAPKs by dephosphorylation. Here, we provide evidence for a role of MKP-1 in the glutamate-induced cell death of HT22 hippocampal cells and primary mouse cortical neurons. We suggest that, during glutamate-induced oxidative stress, protein kinase C (PKC) delta becomes activated and induces sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) through a mechanism that involves degradation of MKP-1. Glutamate-induced activation of ERK1/2 was blocked by inhibition of PKCdelta, confirming that ERK1/2 is regulated by PKCdelta. Prolonged exposure to glutamate caused reduction in the protein level of MKP-1, which correlated with the sustained activation of ERK1/2. Furthermore, knockdown of endogenous MKP-1 by small interfering (si)RNA resulted in pronounced enhancement of ERK1/2 phosphorylation accompanied by increased cytotoxicity under glutamate exposure. In glutamate-treated cells, MKP-1 was polyubiquitylated and proteasome inhibitors markedly blocked the degradation of MKP-1. Moreover, inhibition of glutamate-induced PKCdelta activation suppressed the downregulation and ubiquitylation of MKP-1. Taken together, these results demonstrate that activation of PKCdelta triggers degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby contributing to persistent activation of ERK1/2 under glutamate-induced oxidative toxicity.

PMID:
16537649
DOI:
10.1242/jcs.02837
[Indexed for MEDLINE]
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