| Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. | |
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MedLine Citation:
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PMID: 15542827 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2alpha), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2alpha phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-kappaB) and that eIF2alpha phosphorylation is required for NF-kappaB activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2alpha kinase) to uncouple eIF2alpha phosphorylation from stress and found that phosphorylation of eIF2alpha is both necessary and sufficient to activate both NF-kappaB DNA binding and an NF-kappaB reporter gene. eIF2alpha phosphorylation-dependent NF-kappaB activation correlated with decreased levels of the inhibitor IkappaBalpha protein. Unlike canonical signaling pathways that promote IkappaBalpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated IkappaBalpha levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of IkappaBalpha translation plays an important role in NF-kappaB activation in cells experiencing high levels of eIF2alpha phosphorylation. These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress. |
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Authors:
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Jing Deng; Phoebe D Lu; Yuhong Zhang; Donalyn Scheuner; Randal J Kaufman; Nahum Sonenberg; Heather P Harding; David Ron |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular and cellular biology Volume: 24 ISSN: 0270-7306 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2004 Dec |
Date Detail:
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Created Date: 2004-11-15 Completed Date: 2005-01-04 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 10161-8 Citation Subset: IM |
Affiliation:
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New York University Medical Center, SI 3-10, 540 First Ave., New York, NY 10016, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Cycloheximide / pharmacology Dose-Response Relationship, Drug Endoplasmic Reticulum / metabolism Eukaryotic Initiation Factor-2 / metabolism* Fibroblasts / metabolism Gene Expression Regulation* I-kappa B Proteins / metabolism Immunoblotting Immunoprecipitation Mice NF-kappa B / metabolism* Phosphorylation Protein Biosynthesis* Protein Synthesis Inhibitors / pharmacology RNA, Messenger / metabolism Signal Transduction Stress, Physiological Time Factors Transfection eIF-2 Kinase / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK42394/DK/NIDDK NIH HHS; DK47119/DK/NIDDK NIH HHS; ES08681/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Eukaryotic Initiation Factor-2; 0/I-kappa B Proteins; 0/NF-kappa B; 0/Protein Synthesis Inhibitors; 0/RNA, Messenger; 139874-52-5/NF-kappaB inhibitor alpha; 66-81-9/Cycloheximide; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/eIF-2 Kinase |
| Comments/Corrections | |
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