Identification and Characterization of CCAAT Enhancer-binding Protein (C/EBP) as a Transcriptional Activator for Epstein-Barr Virus Oncogene Latent Membrane Protein 1

被引:17
作者
Noda, Chieko [1 ,2 ]
Murata, Takayuki [1 ]
Kanda, Teru [1 ]
Yoshiyama, Hironori [3 ]
Sugimoto, Atsuko [1 ]
Kawashima, Daisuke [1 ]
Saito, Shinichi [1 ]
Isomura, Hiroki [1 ]
Tsurumi, Tatsuya [1 ,2 ]
机构
[1] Aichi Canc Ctr, Div Virol, Res Inst, Chikusa Ku, Nagoya, Aichi 4648681, Japan
[2] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Oncol, Nagoya, Aichi 4678603, Japan
[3] Hokkaido Univ, Inst Med Genet, Res Ctr Infection Associated Canc, Kita Ku, Sapporo, Hokkaido 0600815, Japan
关键词
HUMAN EPITHELIAL-CELLS; GENE-EXPRESSION; J-KAPPA; REGULATES EXPRESSION; BZLF1; PROTEIN; B-CELLS; PROMOTER; LMP1; MEMBRANE-PROTEIN-1; LYMPHOMA;
D O I
10.1074/jbc.M111.271734
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Epstein-Barr virus LMP1, a major oncoprotein expressed in latent infection, is critical for primary B cell transformation, functioning as a TNFR family member by aggregation in the plasma membrane resulting in constitutive activation of cellular signals, such as NF-kappa B, MAPK, JAK/STAT, and AKT. Although transcription of LMP1 in latent type III cells is generally under the control of the viral coactivator EBNA2, little is known about EBNA2-independent LMP1 expression in type II latency. We thus screened a cDNA library for factors that can activate the LMP1 promoter in an EBNA2-independent manner, using a reporter assay system. So far, we have screened >20,000 clones, and here identified C/EBP epsilon as a new transcriptional activator. Exogenous expression of C/EBP alpha, -beta, or -epsilon efficiently augmented LMP1 mRNA and protein levels in EBV-positive cell lines, whereas other members of the C/EBP family exhibited modest or little activity. It has been demonstrated that LMP1 gene transcription depends on two promoter regions: proximal (ED-L1) and distal (TR-L1). Interestingly, although we first used the proximal promoter for screening, we found that C/EBP increased transcription from both promoters in latent EBV-positive cells. Mutagenesis in reporter assays and EMSA identified only one functional C/EBP binding site, through which activation of both proximal and distal promoters is mediated. Introduction of point mutations into the identified C/EBP site in EBV-BAC caused reduced LMP1 transcription from both LMP1 promoters in epithelial cells. In conclusion, C/EBP is a newly identified transcriptional activator of the LMP1 gene, independent of the EBNA2 coactivator.
引用
收藏
页码:42524 / 42533
页数:10
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