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Combined action of extracellular signal-regulated kinase and p38 kinase rescues Molt4 T cells from nitric oxide-induced apoptotic and necrotic cell death

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Abstract
The mechanisms that regulate nitric oxide (NO)-induced apoptosis, especially in T cell apoptosis, are largely uncharacterized. Here, we report that protection from NO-induced cell death by phorbol 12-myristate 13-acetate (PMA) is dependent on both p38 and extracellular signal-regulated kinase (ERK) activation. Exposure of Molt4 cells to NO donor S-nitroso-N-acetyl-DL- penicillamine (SNAP) induced both apoptotic and necrotic modes of cell death along with a sustained increase in p38 kinase phosphorylation. However, the p38 inhibitor SB202190 only slightly protected Molt4 cells from NO toxicity. In contrast, PMA rapidly phosphorylated both p38 kinase and ERK, and the phosphorylation statuses were not altered in the presence of SNAP. Interestingly, although each mitogen-activated protein kinase (MAPK) inhibitor by itself had only a modest effect, the combination of inhibitors for both MAPKs almost completely abolished the protective effect of PMA. Furthermore, dominant negative or catalytically inactive variants that modulate p38 and ERK mimicked the effects of MAPK inhibitors. We located the action of p38 and ERK upstream of the p53/mitochondrial membrane potential loss and caspases cascade. Together, these findings suggest that the PMA-induced activations of ERK and p38 kinase are parallel events that are both required for inhibition of NO-induced death of Molt4 cells. © 2004 Elsevier Inc. All rights reserved.
Author(s)
Oh, HMChoi, SCLee, HSChun, CHSeo, GSChoi, EYLee, HJLee, MSYeom, JJChoi, SJHan, WCOh, JMChung, YTChun, Jang-SooLee, KMJun, Chang-Duk
Issued Date
2004-08
Type
Article
DOI
10.1016/j.freeradbiomed.2004.04.042
URI
https://scholar.gist.ac.kr/handle/local/18203
Publisher
Elsevier BV
Citation
Free Radical Biology and Medicine, v.37, no.4, pp.463 - 479
ISSN
0891-5849
Appears in Collections:
Department of Life Sciences > 1. Journal Articles
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