| Regulation of tumor necrosis factor-like weak inducer of apoptosis receptor protein (TWEAKR) expression by Kaposi's sarcoma-associated herpesvirus microRNA prevents TWEAK-induced apoptosis and inflammatory cytokine expression. | |
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MedLine Citation:
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PMID: 20844036 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the causative agent of KS, the second most common AIDS-associated malignancy. KSHV expresses at least 18 different mature microRNAs (miRNAs) during latency. To identify cellular targets of KSHV miRNAs, we have analyzed a previously reported series of microarrays examining changes in cellular gene expression in the presence of KSHV miRNAs. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) receptor (TWEAKR) was among the most consistently and robustly downregulated genes in the presence of KSHV miR-K12-10a (miR-K10a). Results from luciferase assays with reporter plasmids containing the 3' untranslated region (UTR) of TWEAKR suggest a targeting of TWEAKR by miR-K10a. The mutation of two predicted miR-K10a recognition sites within the 3' UTR of TWEAKR completely disrupts inhibition by miR-K10a. The expression of TWEAKR was downregulated in cells transfected with miR-K10a as well as during de novo KSHV infection. In a KS tumor-derived endothelial cell line, the downregulation of TWEAKR by miR-K10a resulted in reduced levels of TWEAK-induced caspase activation. In addition, cells transfected with miR-K10a showed less induction of apoptosis by annexin V staining and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays. Finally, the downregulation of TWEAKR by miR-K10a in primary human endothelial cells resulted in a decrease in levels of expression of the proinflammatory cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) in response to TWEAK. These results identify and validate an important cellular target of KSHV miRNAs. Furthermore, we demonstrate that a viral miRNA protects cells from apoptosis and suppresses a proinflammatory response, which may have significant implications in the complex context of KS lesions. |
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Authors:
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Johanna R Abend; Thomas Uldrick; Joseph M Ziegelbauer |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2010-09-15 |
Journal Detail:
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Title: Journal of virology Volume: 84 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-04 Completed Date: 2010-12-20 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 12139-51 Citation Subset: IM |
Affiliation:
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HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Annexin A5 Apoptosis / physiology* Blotting, Western Caspases / metabolism Cell Line Chemokine CCL2 / metabolism DNA Primers / genetics Gene Expression Regulation / physiology* Herpesvirus 8, Human / genetics* Humans In Situ Nick-End Labeling Interleukin-8 / metabolism Luciferases MicroRNAs / genetics, physiology* Mutagenesis Receptors, Tumor Necrosis Factor / genetics, metabolism* Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factors / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Annexin A5; 0/CCL2 protein, human; 0/Chemokine CCL2; 0/DNA Primers; 0/Interleukin-8; 0/MicroRNAs; 0/Receptors, Tumor Necrosis Factor; 0/TNFSF12 protein, human; 0/TWEAK receptor; 0/Tumor Necrosis Factors; EC 1.13.12.-/Luciferases; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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