EB病毒特早期蛋白質Rta促使人類上皮細胞微核生成之研究

Epstein-Barr virus (EBV)為感染性單核球增多症 (infectious mononucleosis)與口黏膜白斑症 (oral hairy leukoplakia)的病原，並且發現與許多人類癌症，例如巴氏淋巴癌 (Burkitt's lymphoma)、何杰金氏淋巴癌 (Hodgin's lymphoma)及鼻咽癌 (nasopharyngeal carcinoma, NPC)等有關。鼻咽癌為發源於鼻咽部上皮細胞的腫瘤，以細胞遺傳學方法分析發現鼻咽癌細胞有基因體不穩定現象，而基因體不穩定與癌症的發生過程息息相關。在NPC活組織切片檢體中發現的EBV相關基因產物主要為潛伏期表現的基因產物，但在這些檢體中亦發現有EBV溶裂期基因的產物。此外，NPC病人的血清中能偵測到較高效價的抗EBV溶裂期基因產物抗體，這些發現提供了EBV溶裂期的進行與NPC發生有關的線索。依據我們實驗室之前的研究，EBV特早期基因BRLF1基因產物Rta會干擾細胞周期行進並造成基因體不穩定，在這篇研究中，更進一步發現Rta可以透過ERK (extracellular signal-regulated kinase)訊息傳遞路徑造成微核生成。細胞經MEK1/2抑制劑U0126處理即能抑制微核生成。同時亦發現表現Rta的細胞中ERK活化程度較高，且細胞中執行絲裂期檢查點的Aurora B kinase活性較低，造成細胞絲裂期較早結束。

關鍵字

EBV ；溶裂期；微核生成；絲裂原活化蛋白激酶訊息傳遞路徑； Aurora B kinase

並列摘要

Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis and oral hairy leukoplakia. It is also associated with several human malignancies, such as Burkitt’s lymphoma, Hodgkin’s lymphoma and nasopharyngeal carcinoma (NPC), etc. NPC is a tumor derived from the epithelial cells of nasal-pharynx. Chromosomal instability has been demonstrated in the tumor cells by cytogenetic analysis. Chromosomal instability is highly associated with the development of cancer cells. Although the major viral products demonstrated in the NPC biopsy samples are derived from latent genes, many lytic gene products are also found in these samples. High antibody titers against viral lytic proteins can be detected in the serum samples obtained from NPC patients. These observations have led to the hypothesis that viral lytic replication is highly associated with the development of NPC. From our previous observation, the viral immediate-early protein Rta, the gene product of BRLF1 is able to interfere with the cell cycle progression and induce chromosomal instability. In this study we further demonstrate that Rta-induced micronucleus formation is mediated through the extracellular signal-regulated kinase (ERK) signaling pathway. In the presence of MEK1/2 inhibitor, U0126, the micronucleus formation ability is blocked. Enhanced ERK phosphorylation can be detected in cells expressing Rta protein. The kinase activity of the mitotic checkpoint protein, Aurora B kinase, is decreased and consequently leading to an early exist from the mitotic phase is demonstrated in Rta expressed cells.

並列關鍵字

EBV ； Rta ； ERK ； Aurora B kinase ； micronuclei formation

參考文獻

高歆嵐 (2006). EBV Rta enhances micronucleus formation, DNA strand break and accelerates M phase progression in human epithelial cells. Graduate institute of Microbiology, College of Medicine, National Taiwan University, Master thesis

Lo, K. W., Teo, P. M., Hui, A. B., To, K. F., Tsang, Y. S., Chan, S. Y., Mak, K. F., Lee, J. C. and Huang, D. P. (2000). High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res 60, 3348-53.

Chang, Y., Tung, C. H., Huang, Y. T., Lu, J., Chen, J. Y. and Tsai, C. H. (1999). Requirement for cell-to-cell contact in Epstein-Barr virus infection of nasopharyngeal carcinoma cells and keratinocytes. J Virol 73, 8857-66.

Spruck, C. H., 3rd, Tsai, Y. C., Huang, D. P., Yang, A. S., Rideout, W. M., 3rd, Gonzalez-Zulueta, M., Choi, P., Lo, K. W., Yu, M. C. and Jones, P. A. (1992). Absence of p53 gene mutations in primary nasopharyngeal carcinomas. Cancer Res 52, 4787-90.

Sheikh, M. S., Li, X. S., Chen, J. C., Shao, Z. M., Ordonez, J. V. and Fontana, J. A. (1994). Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways. Oncogene 9, 3407-15.

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EB病毒特早期蛋白質Rta促使人類上皮細胞微核生成之研究

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