Protein kinase C delta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death
SCIE
SCOPUS
- Title
- Protein kinase C delta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death
- Authors
- Choi, BH; Hur, EM; Lee, JH; Jun, DJ; Kim, KT
- Date Issued
- 2006-04-01
- Publisher
- COMPANY OF BIOLOGISTS LTD
- 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 PKC delta, confirming that ERK1/2 is regulated by PKC delta. 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 PKC delta activation suppressed the downregulation and ubiquitylation of MKP-1. Taken together, these results demonstrate that activation of PKC delta triggers degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby contributing to persistent activation of ERK1/2 under glutamate-induced oxidative toxicity.
- Keywords
- glutamate; MKP-1; immature cortical neuron; neuronal cell death; ubiquitylation; proteasomal degradation; OXIDATIVE STRESS; TYROSINE PHOSPHORYLATION; PROTEOLYTIC ACTIVATION; INDUCED APOPTOSIS; DOPAMINERGIC DEGENERATION; CONDITIONAL EXPRESSION; CEREBRAL-ISCHEMIA; INDUCTION; RECEPTOR; PATHWAY
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/24091
- DOI
- 10.1242/JCS.02837
- ISSN
- 0021-9533
- Article Type
- Article
- Citation
- JOURNAL OF CELL SCIENCE, vol. 119, no. 7, page. 1329 - 1340, 2006-04-01
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