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Regulation of Epstein-Barr virus replication by signal transduction

通过信号转导调节 Epstein-Barr 病毒复制

基本信息

批准号：
17590415
负责人：
SHIRAKATA Masaki
金额：
$ 2.24万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590415/
关键词：
EBV replication transcriptional regulation シグナル伝達 MAPK EBV

项目摘要

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 … More 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

EB病毒(Epstein-Barr Virus，EBV)是一种人类疱疹病毒，是传染性单核细胞增多症和慢性活动性EBV感染的病原体，也被称为与Burkitt淋巴瘤、鼻咽癌相关的DNA肿瘤病毒。一些报告还表明，EBV也与自身免疫性疾病有关。在健康人中，EBV的生命周期与B细胞的发育密切相关，EBV隐藏在潜伏状态，不会导致任何疾病。因此，了解EBV的生命周期在患者体内是如何紊乱或紊乱的，对于了解EBV相关疾病的发病机制和寻找有效的治疗方法具有重要意义。在以前的报告中，我们发现从潜在复制起点ORIP开始的DNA复制受到p38MAPK信号转导的负调控。这一发现使我们确定了EBNA1的磷酸化氨基酸及其在EBNA1功能中的作用。通过对几个EBNA1突变体的磷酸化检测，我们发现Ser383和Ser383的…有393个氨基酸主要是磷酸化氨基酸。位于这些残基之间的丝氨酸Ser385、Ser386、Ser388和Ser389被弱磷酸化。Ser383和Ser393附近的氨基酸序列与MAPK的共同序列相同，表明这些残基是这些激酶的潜在靶点。然后，我们检查了用Ala取代这些Ser的EBNA1突变体的复制活性，发现这些突变使活性降低了50%。这一结果提示EBNA1的磷酸化可能对EBV的复制有一定的促进作用，但不能解释p38MAPK是如何抑制ORIP的复制的。因此，我们现在研究了p38MAPK调节宿主细胞复制机制的另一种可能性。我们还检测了磷酸化位点突变对转录调控的影响。已知EBNA1可促进EBV CP启动子转录，抑制QP启动子转录。我们发现，磷酸化位点的突变减少了CP的转录，而对QP没有影响。这提示EBNA1的磷酸化可能在EBV潜伏期的调节中起重要作用。较少

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The adaptor-like protein ROG-1 is required for activation of the Ras-MAP kinase pathway and meiotic cell cycle progression in Caenorhabditis elegans.

接头样蛋白 ROG-1 是激活 Ras-MAP 激酶途径和秀丽隐杆线虫减数分裂细胞周期进程所必需的。

DOI：
发表时间：
2007
期刊：
Genes Cells 12
影响因子：
0
作者：
Yosuke Matsubara;Ichiro Kawasaki;Seiichi Urushiyama;Tomoharu Yasuda;Masaki Shirakata;Yuichi Iino;Hiroshi Shibuya;Yuji Yamanashi.
通讯作者：
Yuji Yamanashi.

Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases

DOI：
10.1111/j.1365-2443.2006.00926.x
发表时间：
2006-02-01
期刊：
GENES TO CELLS
影响因子：
2.1
作者：
Honma, M;Higuchi, O;Yamanashi, Y
通讯作者：
Yamanashi, Y

IL-2-regulated persistent human herpesvirus-GB infection facilitates growth of adult T cell leukemia cells.

IL-2 调节的持续人类疱疹病毒 GB 感染促进成人 T 细胞白血病细胞的生长。

DOI：
发表时间：
2006
期刊：
Genes Cells 11
影响因子：
0
作者：
Kang MS;Yasui;T;Kieff;E.;et al.;Miyuki Honma
通讯作者：
Miyuki Honma

IL-2-regulated persistent human herpesvirus-6B infection facilitates growth of adult T cell leukemia cells.

IL-2 调节的持续性人类疱疹病毒 6B 感染促进成人 T 细胞白血病细胞的生长。

DOI：
发表时间：
2005
期刊：
J. Med. Dent. Sci 52
影响因子：
0
作者：
Kawano MA;Inoue T;Tsukamoto H;Takaya T;Enomoto T;Takahashi R;Yokoyama N;Yamamoto N;Nakanishi A;Imai T;Wada T;Kataoka K;Handa H.;Ojima T
通讯作者：
Ojima T

IL-2 regulated persistent human herpesvirus-6B infection facilitates growth of adult T cell leukemia cells.

IL-2 调节的持续人类疱疹病毒 6B 感染促进成人 T 细胞白血病细胞的生长。