EBV EXPRESSION IN NASOPHARYNGEAL CARCINOMA

本研究的目的是确定EBV在鼻咽癌（NPC）病因学中的作用，鼻咽癌是一种上皮恶性肿瘤，在中国南方、北方非洲和爱斯基摩人中发病率很高。 在NPC中表达的病毒基因包括潜伏膜蛋白，LMP 1和2，以及通过BamHI A片段转录的mRNA家族，其可能编码四种先前未鉴定的蛋白质。LMP 1与肿瘤坏死因子受体（TNFR）相关因子（TRAFS）相互作用，通过该相互作用，LMP 1激活NfkappaB转录因子和JNK激酶。 我们已经表明，LMP 1诱导表皮生长因子受体（EGFR）的表达，通过TRAF相互作用域和突变的TRAF相互作用产生了两个突变体，是温度敏感的EGFR诱导。 我们已经确定LMP 1的两个激活结构域诱导不同形式的NfkappaB转录因子。 我们还发现LMP 1通过诱导A20抑制p53介导的细胞凋亡。在本研究中，我们将进一步分析LMP 1介导的转化的生化基础以及LMP 2和BamHI-A蛋白在上皮细胞中的生物学和生化特性。我们的具体目标是1）表征在上皮细胞中由LMP 1激活的信号转导途径，其激活不同形式的NfkappaB，并鉴定受这些途径影响的细胞基因，2）确定LMP 1和A20表达对p53介导的细胞凋亡的影响，3）分析上皮细胞中的LMP 2抑制并鉴定受LMP 2表达影响的生化途径，4）鉴定细胞系和NPC肿瘤中由BamHI A开放阅读框编码的蛋白质，5）确定RK-BARF 0与Notch的相互作用对Notch信号传导的影响，6）确定BamHI A蛋白的表达对病毒和细胞表达的影响.

The goal of this research is to determine the role of EBV in the etiology of nasopharyngeal carcinoma (NPC), an epithelial malignancy that develops with high incidence in Southern China, Northern Africa, and among Eskimoes. The viral genes that are expressed in NPC include the latent membrane proteins, LMP1 and 2, and a family of mRNAs, transcribed through the BamHI A fragment, that potentially encode four previously unidentified proteins. LMP1 interacts with the tumor necrosis factor receptor (TNFR) associated factors (TRAFS) through which it activates the NfkappaB transcription factor and JNK kinase. We have shown that LMP1 induces the expression of epidermal growth factor receptor (EGFR) through the TRAF interacting domain and by mutating the TRAF interacting have produced two mutants that are temperature sensitive with regard to EGFR induction. We have determined that the two activation domains of LMP1 induce distinct forms of the NfkappaB transcription factor. We have also shown that LMP1 inhibits p53-mediated apoptosis through induction of A20. In this grant, we will further analyze the biochemical basis of LMP1-mediated transformation and the biologic and biochemical properties of LMP2 and the BamHI A proteins in epithelial cells. Our specific aims are to 1) Characterize the signal transduction pathways activated by LMP1 in epithelial cells that activate distinct forms of NfkappaB and identify the cellular genes that are affected by these pathways, 2) Determine the effect of LMP1 and A20 expression on p53-mediated apoptosis, 3) Analyze LMP2 suppression in epithelial cells and identify the biochemical pathways affected by LMP2 expression, 4) Identify the proteins encoded by the BamHI A open reading frames in cell lines and in NPC tumors, 5) Determine the effect of the interaction of RK- BARF0 with Notch on Notch signaling, 6) Determine the effects of expression of the BamHI A proteins on viral and cellular expression.