Journal
JOURNAL OF VIROLOGY
Volume 82, Issue 4, Pages 1946-1958Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02136-07
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Funding
- NCI NIH HHS [R01 CA124311] Funding Source: Medline
- NCRR NIH HHS [P20 RR020152] Funding Source: Medline
- NIAID NIH HHS [R01 AI057481-02, R01 AI057481-03, R01 AI057481] Funding Source: Medline
- NIDCR NIH HHS [R21-DE17008, R21 DE017008] Funding Source: Medline
- NIGMS NIH HHS [R01-GM48045, R01 GM048045] Funding Source: Medline
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The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of nuclear factor kappa B (NF-kappa B). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative reverse transcription-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappa B binding sites in the miR-146a promoter and identified a role for an Oct-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a-expres sing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon-responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response.
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