| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Epstein-Barr virus (EBV) is a human herpesvirus that is causal reagent of infectious mononucleosis and chronic active EBV infection and also known as a DNA tumor virus associated with Burkitt's lymphoma, nasophangal carcinoma. Several reports also indicate that EBV is also associated with autoimmune diseases. In a healthy person, the life cycle of EBV is deeply related to B cell development, and EBV hides itself in a latent state and does not cause any diseases. Therefore, it is important to know how the life cylcle of EBV is disordered or disturbed in patients to understand pathogenesis and find effective treatments for EBV associated diseases. In the previous report, we found that DNA replication from the latent replication origin oriP is negatively regulated by signal transduction through p38 MAPK. This finding lead us to identify phosphorylated amino acids of EBNA1 and their roles in EBNA1 functions. By examined phosphorylation of several EBNA1 mutants, we found that Ser383 and Ser
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393 are mainly phosphorylated amino acids. Serins located between these residues, Ser385, Ser386, Ser388 and Ser389 are phosphorylated weakly. Amino acid sequences around Ser383 and Ser393 are idential to the consensus sequence of MAPKs indicating that these residues are potential targets of these kinases. We then examined replication activity of the EBNA1 mutants that replaced these Ser with Ala, and found that the activity was reduced 50% by these mutations. This result suggests that phosphorylation of EBNA1 may have some enhancing effect to EBV replication, but it does not explain how p38 MAPK suppress replication of oriP. Therefore, we now examined another possibility that p38 MAPK modulates the replication machinery of host cells. We also examined effects of mutations at phosphorylation sites on transcriptional regulation. It is known that EBNA1 enhances transcription from EBV Cp promoter and suppress Qp promoter. We found that mutation at phosphorylation sites reduces transcription from Cp and have no effects on Qp. This suggests that phosphorylation of EBNA1 may be important in the regulation of latency of EBV. Less
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