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Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death.
J Cell Sci. 2006 Apr 01; 119(Pt 7):1329-40.JC

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16537649

Citation

Choi, Bo-Hwa, et al. "Protein Kinase Cdelta-mediated Proteasomal Degradation of MAP Kinase Phosphatase-1 Contributes to Glutamate-induced Neuronal Cell Death." Journal of Cell Science, vol. 119, no. Pt 7, 2006, pp. 1329-40.
Choi BH, Hur EM, Lee JH, et al. Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. J Cell Sci. 2006;119(Pt 7):1329-40.
Choi, B. H., Hur, E. M., Lee, J. H., Jun, D. J., & Kim, K. T. (2006). Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. Journal of Cell Science, 119(Pt 7), 1329-40.
Choi BH, et al. Protein Kinase Cdelta-mediated Proteasomal Degradation of MAP Kinase Phosphatase-1 Contributes to Glutamate-induced Neuronal Cell Death. J Cell Sci. 2006 Apr 1;119(Pt 7):1329-40. PubMed PMID: 16537649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. AU - Choi,Bo-Hwa, AU - Hur,Eun-Mi, AU - Lee,Jong-Hee, AU - Jun,Dong-Jae, AU - Kim,Kyong-Tai, Y1 - 2006/03/14/ PY - 2006/3/16/pubmed PY - 2006/6/6/medline PY - 2006/3/16/entrez SP - 1329 EP - 40 JF - Journal of cell science JO - J Cell Sci VL - 119 IS - Pt 7 N2 - 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. SN - 0021-9533 UR - https://www.unboundmedicine.com/medline/citation/16537649/Protein_kinase_Cdelta_mediated_proteasomal_degradation_of_MAP_kinase_phosphatase_1_contributes_to_glutamate_induced_neuronal_cell_death_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=16537649 DB - PRIME DP - Unbound Medicine ER -