An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.
An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.
复制标题
ATM/Chk2介导的DNA损伤响应信号通路可抑制原代人类B细胞的Epstein-Barr病毒转化。
DOI：
10.1016/j.chom.2010.11.004
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发表时间：
2010-12-16
影响因子：
30.3
通讯作者：
Luftig MA
中科院分区：
文献类型：
--
作者：
Nikitin PA;Yan CM;Forte E;Bocedi A;Tourigny JP;White RE;Allday MJ;Patel A;Dave SS;Kim W;Hu K;Guo J;Tainter D;Rusyn E;Luftig MA
Epstein-Barr病毒（EBV）是一种引起人类恶性肿瘤的致癌疱疹病毒，其在体外感染原代人类B细胞并使其永生化为无限增殖的淋巴母细胞样细胞系，其代表EBV诱导的肿瘤发生的模型。永生化效率非常低，表明先天性肿瘤抑制机制是有效的。我们确定的DNA损伤反应（DDR）作为一个重要组成部分的潜在的肿瘤抑制机制。EBV诱导的DDR激活不是由于裂解性病毒复制，DDR标记也不与潜伏附加体共定位。相反，EBV诱导的过度增殖的短暂时期与DDR激活相关。抑制DDR激酶ATM和Chk 2显著增加原代B细胞的转化效率。此外，病毒潜伏癌蛋白EBNA 3C是减弱EBV诱导的DNA损伤反应所必需的。我们提出，早期细胞分裂中致癌活性的提高激活了生长抑制性DDR，其被病毒潜伏产物减弱以诱导细胞永生化。
Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication nor did the DDR marks co-localize with latent episomes. Rather, a transient period of EBV-induced hyper-proliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoproteins EBNA3C was required to attenuate the EBV-induced DNA damage response We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR which is attenuated by viral latency products to induce cell immortalization.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
6.7
作者：
Hertle ML;Popp C;Petermann S;Maier S;Kremmer E;Lang R;Mages J;Kempkes B
通讯作者：
Kempkes B
影响因子：
7.3
作者：
Arienti, KL;Brunmark, A;Breitenbucher, JG
通讯作者：
Breitenbucher, JG