Nucleic Acids Research Advance Access published online on October 21, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn666
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Molecular Biology |
Epstein–Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-
B pathway
Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
*To whom correspondence should be addressed. Tel: +39 081 7463627; Fax: +39 081 7463205; Email: mallardo{at}dbbm.unina.it
Received August 8, 2008. Revised September 15, 2008. Accepted September 21, 2008.
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-
B (NF-B). 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-B binding sites in the miR-155 promoter; both sites recruited NF-B 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-B 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-B 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.
Present address: Sven Kroening, Universitätsklinikum Erlangen, Medizinische Klinik 4, Erlagen, DE, Germany
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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