期刊
LEUKEMIA & LYMPHOMA
卷 54, 期 9, 页码 2035-2040出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/10428194.2013.769218
关键词
LMP1; Egr-1; AID; Rassf6; EBV; B cell lymphoma
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2011-0010951]
- Samsung Biomedical Research Institute [C-B1-107]
- National Research Foundation of Korea [2011-0010951] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1) is a transmembrane protein essential for EBV-induced immortalization and transformation of B cells. Activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Here, we report an intracellular mechanism by which LMP1 contributes to B cell lymphomagenesis via AID expression. In our experiments, LMP1 increased AID mRNA expression and promoter activity. The AID promoter region contains a binding site for Egr-1, a prominent transcription factor that is reported to be up-regulated by LMP1. In promoter activity analysis, Egr-1 enhanced the reporter activity of the wild-type AID promoter, but not that containing a mutated Egr-1 binding site. Egr-1 knockdown abrogated LMP-1-mediated up-regulation of AID promoter reporter activity in EBV-negative BJAB cells and reduced AID promoter reporter activity in EBV-positive SKW6.4 cells. AID induced down-regulation of the nuclear factor-kappa B (NF kappa B) inhibitory tumor suppressor Rassf6, suggesting that AID functions as an upstream regulator of the NF. B inhibitory Rassf6. Moreover, Egr-1 expression was associated with an increased number of genomic lesions in genome-wide analysis using single nucleotide polymorphism (SNP) microarray and copy number variation (CNV). Collectively, LMP1 induces AID up-regulation and genomic instability via Egr-1. Increased AID expression may, in turn, promote down-regulation of the NF. B inhibitor, Rassf6, thereby further increasing the survival of genetically destabilized B-cell lymphoma cells.
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