Krauer Kenia G, Burgess Andrew, Buck Marion, Flanagan James, Sculley Tom B, Gabrielli Brian
Queensland Institute of Medical Research and Joint Oncology Program, University of Queensland, Brisbane, Australia.
Oncogene. 2004 Feb 19;23(7):1342-53. doi: 10.1038/sj.onc.1207253.
The Epstein-Barr nuclear antigens (EBNA), EBNA-3, -4 and -6, have previously been shown to act as transcriptional regulators, however, this study identifies another function for these proteins, disruption of the G2/M checkpoint. Lymphoblastoid cell lines (LCLs) treated with a G2/M initiating drug azelaic bishydroxamine (ABHA) did not show a G2/M checkpoint response, but rather they display an increase in cell death, a characteristic of sensitivity to the cytotoxic effects of the drug. Cell cycle analysis demonstrated that the individual expression of EBNA-3, -4 or -6 are capable of disrupting the G2/M checkpoint response induced by ABHA resulting in increased toxicity, whereas EBNA-2, and -5 were not. EBNA-3 gene family protein expression also disrupted the G2/M checkpoint initiated in response to the genotoxin etoposide and the S phase inhibitor hydroxyurea. The G2 arrest in response to these drugs were sensitive to caffeine, suggesting that ATM/ATR signalling in these checkpoint responses may be blocked by the EBNA-3 family proteins. The function of EBNA-3, -4 and -6 proteins appears to be more complex than anticipated and these data suggest a role for these proteins in disrupting the host cell cycle machinery.
此前已证明，爱泼斯坦-巴尔核抗原（EBNA）中的EBNA-3、-4和-6可作为转录调节因子，然而，本研究确定了这些蛋白质的另一种功能，即破坏G2/M期检验点。用G2/M期起始药物壬二酸双羟胺（ABHA）处理的淋巴母细胞系（LCL）未表现出G2/M期检验点反应，反而细胞死亡增加，这是对该药物细胞毒性作用敏感的特征。细胞周期分析表明，单独表达EBNA-3、-4或-6能够破坏由ABHA诱导的G2/M期检验点反应，导致毒性增加，而EBNA-2和-5则不能。EBNA-3基因家族蛋白的表达也破坏了因基因毒素依托泊苷和S期抑制剂羟基脲而引发的G2/M期检验点。对这些药物产生的G2期阻滞对咖啡因敏感，这表明这些检验点反应中的ATM/ATR信号传导可能被EBNA-3家族蛋白阻断。EBNA-3、-4和-6蛋白的功能似乎比预期的更为复杂，这些数据表明这些蛋白在破坏宿主细胞周期机制中发挥作用。
