| Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation. | |
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MedLine Citation:
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PMID: 20448643 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of nuclear factor-κB (NF-κB) activation and apoptosis in tumor necrosis factor (TNF) receptor 1 signaling pathway. Although the molecular basis for the anti-NF-κB function of A20 has been well elucidated, the anti-apoptotic function of A20 is largely unknown. Here, we report a novel mechanism underlying the anti-apoptotic function of A20: A20 blocks TNF-induced apoptosis through suppression of c-jun N-terminal kinase (JNK) by targeting apoptosis signal-regulating kinase1 (ASK1). First, the ectopic expression of A20 drastically inhibits TNF-induced JNK activation and apoptosis in multiple cell types including those deficient of NF-κB activation. Unexpectedly, the blunting effect of A20 on TNF-induced JNK activation is not mediated by affecting the TNFR1 signaling complex formation. Instead, A20 interacts with ASK1, an important MAPKK kinase in the JNK signaling cascade. More importantly, overexpression of wild-type A20, but not of mutant A20 (ZnF4; C624A, C627A), promotes degradation of the ASK1 through the ubiquitin-proteasome system. Taken together, the results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway: A20 binds to ASK1 and mediates ASK1 degradation, leading to suppression of JNK activation and eventually blockage of apoptosis. |
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Authors:
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M Won; K A Park; H S Byun; K-C Sohn; Y-R Kim; J Jeon; J H Hong; J Park; J H Seok; J M Kim; W-H Yoon; I-S Jang; H M Shen; Z G Liu; G M Hur |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-07 |
Journal Detail:
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Title: Cell death and differentiation Volume: 17 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 1830-41 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, Daejeon, Korea. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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