| Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3'-kinase (PI3K) pathway is inhibited. | |
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MedLine Citation:
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PMID: 12879014 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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c-Jun N-terminal kinase (JNK) is activated when cells are exposed to noxious stimuli. The role of JNK in apoptosis is subject to considerable debate; for example, JNK activation may promote or inhibit apoptosis depending on the cell type and stimulus involved. These conflicting results have arisen in part because few studies have successfully separated JNK activation from the primary stress-induced damage or from other stress-induced signalling pathways. Here we describe a conditional mutant, deltaMEKK1:ER*, which allows selective activation of the JNK cascade in the absence of any cellular stress. Activation of deltaMEKK1:ER* in CC139 fibroblasts resulted in the rapid and sustained activation of JNK without activating ERK or p38 or promoting IkappaBalpha phosphorylation. Activation of deltaMEKK1:ER* caused a reversible halt in cell growth but failed to induce apoptosis. In contrast, treatment of cells with LY294002, to inhibit phosphoinositide 3-kinase (PI3K), caused downregulation of Bcl-2 and Mcl-1 and allowed deltaMEKK1:ER* to elicit a robust apoptotic response characterized by activation of Bax and caspases. This PI3K-inhibitable, JNK-induced death response was not impeded, but actually accelerated, by cycloheximide. This suggests that JNK-induced activation of Bax and cell death does not require the upregulation of pro-death genes such as Bim or FasL, but rather proceeds through pre-existing components. However, if the PI3K cell survival pathway is not inhibited, even sustained activation of JNK exerts no overt proapoptotic effect in CC139 cells. |
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Authors:
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Sarah A Molton; Daniel E Todd; Simon J Cook |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Oncogene Volume: 22 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2003 Jul |
Date Detail:
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Created Date: 2003-07-24 Completed Date: 2003-11-07 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 4690-701 Citation Subset: IM |
Affiliation:
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Inositide Laboratory, Signalling Programme, The Babraham Institute, Cambridge CB2 4AT, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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antagonists & inhibitors*,
metabolism Animals Apoptosis* Blotting, Western Carrier Proteins / metabolism Cell Cycle Cell Death Cell Line Cell Survival Cricetinae Down-Regulation Enzyme Activation Fibroblasts / metabolism Gentian Violet I-kappa B Proteins / metabolism JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases / genetics, metabolism* Mutation Phosphorylation Plasmids / metabolism Protein Conformation Protein Structure, Tertiary Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-bcl-2* Rats Signal Transduction Time Factors Transfection bcl-2-Associated X Protein p38 Mitogen-Activated Protein Kinases |
| Chemical | |
Reg. No./Substance:
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0/Bax protein, rat; 0/Carrier Proteins; 0/I-kappa B Proteins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 139874-52-5/NF-kappaB inhibitor alpha; 548-62-9/Gentian Violet; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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