The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes
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- Regina Feederle
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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- Janina Haar
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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- Katharina Bernhardt
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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- Sarah D. Linnstaedt
- Center for Virology, and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
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- Helmut Bannert
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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- Helge Lips
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
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- Bryan R. Cullen
- Center for Virology, and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
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- Henri-Jacques Delecluse
- German Cancer Research Centre, DKFZ, ATV-F100, Pathology of Virus-Associated Tumours, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
抄録
<jats:title>ABSTRACT</jats:title> <jats:p> Epstein-Barr virus (EBV) transforms B lymphocytes through the expression of the latent viral proteins EBNA and latent membrane protein (LMP). Recently, it has become apparent that microRNAs (miRNAs) also contribute to EBV's oncogenic properties; recombinant EBVs that lack the BHRF1 miRNA cluster display a reduced ability to transform B lymphocytes <jats:italic>in vitro</jats:italic> . Furthermore, infected cells evince a marked upregulation of the EBNA genes. Using recombinant viruses that lack only one member of the cluster, we now show that all three BHRF1 miRNAs contribute to B-cell transformation. Recombinants that lacked miR-BHRF1-2 or miR-BHRF1-3 displayed enhanced EBNA expression initiated at the Cp and Wp promoters. Interestingly, we find that the deletion of miR-BHRF1-2 reduced the expression level of miR-BHRF1-3 and possibly that of miR-BHRF1-1, demonstrating that the expression of one miRNA can potentiate the expression of other miRNAs located in the same cluster. Therefore, the phenotypic traits of the miR-BHRF1-2 null mutant could result partly from reduced miR-BHRF1-1 and miR-BHRF1-3 expression levels. Nevertheless, using an miR-BHRF1-1 and miR-BHRF1-3 double mutant, we could directly assess and confirm the contribution of miR-BHRF1-2 to B-cell transformation. Furthermore, we found that the potentiating effect of miR-BHRF1-2 on miR-BHRF1-3 synthesis can be reproduced with simple expression plasmids, provided that both miRNAs are processed from the same transcript. Therefore, this enhancing effect does not result from an idiosyncrasy of the EBV genome but rather reflects a general property of these miRNAs. This study highlights the advantages of arranging the BHRF1 miRNAs in clusters: it allows the synchronous and synergistic expression of genetic elements that cooperate to transform their target cells. </jats:p>
収録刊行物
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- Journal of Virology
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Journal of Virology 85 (19), 9801-9810, 2011-10
American Society for Microbiology