Journal Article

Epstein–Barr virus latent membrane protein 1 <i>trans</i>-activates miR-155 transcription through the NF-κB pathway

Graziana Gatto, Annalisa Rossi, Daniela Rossi, Sven Kroening, Stefano Bonatti and Massimo Mallardo

in Nucleic Acids Research

Volume 36, issue 20, pages 6608-6619
Published in print November 2008 | ISSN: 0305-1048
Published online October 2008 | e-ISSN: 1362-4962 | DOI: http://dx.doi.org/10.1093/nar/gkn666

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The Epstein–Barr virus (EBV)-encoded latent membrane protein-1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, substantially contributes to EBV's oncogenic potential by activating nuclear factor-κB (NF-κB). miR-155 is an oncogenic miRNA critical for B-cell maturation and immunoglobulin production in response to antigen. We report that miR-155 expression is much higher in EBV-immortalized B cells than in EBV-negative B cells. LMP1, but not LMP2, up-regulated the expression of miR-155, when transfected in EBV-negative B cells. We analyzed two putative NF-κB binding sites in the miR-155 promoter; both sites recruited NF-κB complex, in nuclear extract from EBV-immortalized cells. The exogenous expression of LMP1, in EBV-negative background, is temporally correlated to induction of p65 with binding on both NF-κB sites and with miR-155 overexpression. The induction of p65 binding together with increased RNA polymerase II binding, confirms that LMP1-mediated activation of miR-155 occurs transcriptionally. In reporter assays, miR-155 promoter lacking NF-κB binding sites was no longer activated by LMP1 expression and an intact AP1 site is needed to attain maximum activation. Finally, we demonstrate that LMP1-mediated activation of miR-155 in an EBV-negative background correlates with reduction of protein PU.1, which is a possible miR target.

Journal Article.  7062 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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