Kilger E, Kieser A, Baumann M, Hammerschmidt W
GSF-National Research Center for Environment and Health, Institut f¿r Klinische Molekularbiologie und Tumorgenetik, Marchioninistr. 25, D-81377 Munich, Germany.
EMBO J. 1998 Mar 16;17(6):1700-9. doi: 10.1093/emboj/17.6.1700.
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is essential for the immortalization of human B cells and is linked etiologically to several human tumors. LMP1 is an integral membrane protein which acts like a constitutively active receptor. It binds tumor necrosis factor (TNF)-receptor-associated factors (TRAFs), activates NF-kappaB and triggers the transcription factor AP-1 via the c-Jun N-terminal kinase (JNK) cascade, but its specific contribution to B-cell immortalization has not been elucidated fully. To address the function of LMP1, we established B cell lines with a novel mini-EBV plasmid in which the LMP1 gene can be regulated at will without affecting the expression of other latent EBV genes. We demonstrate here that continuous expression of LMP1 is essential for the proliferation of EBV-immortalized B cells in vitro. Re-induction of LMP1 expression or activation of the cellular CD40 receptor both induce the JNK signaling cascade, activate the transcription factor NF-kappaB and stimulate proliferation of these B cells. Our findings strongly suggest that LMP1 mimics B-cell activation processes which are physiologically triggered by CD40-CD40 ligand signals. Since LMP1 acts in a ligand-independent manner, it replaces the T cell-derived activation signal to sustain indefinite B-cell proliferation.
爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白1（LMP1）对于人B细胞的永生化至关重要，并且在病因学上与多种人类肿瘤相关。LMP1是一种整合膜蛋白，其作用类似于组成型活性受体。它结合肿瘤坏死因子（TNF）受体相关因子（TRAFs），激活核因子κB（NF-κB）并通过c-Jun氨基末端激酶（JNK）级联反应触发转录因子AP-1，但它对B细胞永生化的具体贡献尚未完全阐明。为了研究LMP1的功能，我们用一种新型的微型EBV质粒建立了B细胞系，在该质粒中LMP1基因可以随意调控而不影响其他EBV潜伏基因的表达。我们在此证明，LMP1的持续表达对于EBV永生化B细胞在体外的增殖至关重要。LMP1表达的重新诱导或细胞CD40受体的激活均诱导JNK信号级联反应，激活转录因子NF-κB并刺激这些B细胞的增殖。我们的发现强烈表明，LMP1模拟了由CD40-CD40配体信号在生理上触发的B细胞激活过程。由于LMP1以不依赖配体的方式起作用，它取代了T细胞衍生的激活信号以维持B细胞的无限增殖。
