Institute of Basic Medicine, Shandong Academy of Medical Science, Key Medical Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Jinan 250062, PR China.
Mol Immunol. 2010 May;47(9):1783-92. doi: 10.1016/j.molimm.2010.02.017. Epub 2010 Mar 24.
In the present study, we show that the treatment of Epstein-Barr virus (EBV) latently infected Raji cells with TPA/SB caused the cell growth arrest. The Zta-positive cells were predominantly enriched in G0/G1 phase of cell cycle. When Zta expression reached a maximal level, a fraction of Zta expressing cell population reentered S phase. Analysis of the expression pattern of a key set of cell cycle regulators revealed that the expression of Zta and Rta substantially interfered with the cell cycle regulatory machinery in Raji cells, strongly inhibiting the expression of Rb and p53 and inducing the expression of E2F1. Down-regulation of Rb was further demonstrated to be mediated by proteasomal degradation, and p53 and p21 affected at transcription level. The data indicate that both Zta and Rta promote entry into S phase of Raji cells. The important roles of Zta and Rta in EBV lytic reactivation were also demonstrated. Our finding suggests that these two transcriptional activators may act synergistically to govern the expression of downstream early and late genes as well as cellular genes and initiation of lytic cycle and manipulation of cell cycle regulatory mechanisms require the joint and interactive contributions of Rta and Zta.
在本研究中，我们表明，用 TPA/SB 处理潜伏感染 EBV 的 Raji 细胞会导致细胞生长停滞。Zta 阳性细胞主要富集在细胞周期的 G0/G1 期。当 Zta 表达达到最高水平时，一部分表达 Zta 的细胞群重新进入 S 期。对一组关键细胞周期调节剂表达模式的分析表明，Zta 和 Rta 的表达严重干扰了 Raji 细胞的细胞周期调节机制，强烈抑制了 Rb 和 p53 的表达，并诱导了 E2F1 的表达。进一步的研究表明，Rb 的下调是通过蛋白酶体降解介导的，而 p53 和 p21 在转录水平受到影响。这些数据表明，Zta 和 Rta 都促进了 Raji 细胞进入 S 期。还证明了 Zta 和 Rta 在 EBV 裂解激活中的重要作用。我们的发现表明，这两个转录激活因子可能协同作用，共同调控下游早期和晚期基因以及细胞基因的表达，并启动裂解周期，而对细胞周期调控机制的操纵需要 Rta 和 Zta 的共同和交互作用。
