Cannell E J, Farrell P J, Sinclair A J
Ludwig Institute for Cancer Research, Imperial College School of Medicine at St. Mary's Hospital, London, UK.
Oncogene. 1996 Oct 3;13(7):1413-21.
Infection of human primary B-lymphocytes with Epstein-Barr virus (EBV) drives quiescent cells into continual proliferation and results in the outgrowth of immortal cell lines. This requires re-programming of the mechanisms that, in the absence of appropriate antigenic stimulation, normally prevent the proliferation of B-lymphocytes. Since the Retinoblastoma protein (pRb) and its relatives, p107 and p130, play critical roles in controlling the mammalian cell division cycle, we have investigated the expression and phosphorylation status of these proteins following EBV immortalisation of primary B-lymphocytes. In this report, we show that EBV drives the hyperphosphorylation of pRb. This is achieved by a strategy involving the altered expression of several components of the signal transduction pathway that normally regulates the phosphorylation status of pRb, including the up regulation of a number of cyclins and cyclin-dependent kinases and the down regulation of a subset of cyclin-dependent kinase inhibitors. The net result is the formation of active cyclin-dependent kinase complexes that are capable of phosphorylating and inactivating pRb. The results presented here identify the activation of a normal signal transduction pathway as an important component of the strategy used by EBV to drive cell proliferation.
用爱泼斯坦-巴尔病毒（EBV）感染人类原代B淋巴细胞会促使静止细胞持续增殖，并导致永生细胞系的生长。这需要对在缺乏适当抗原刺激时通常阻止B淋巴细胞增殖的机制进行重新编程。由于视网膜母细胞瘤蛋白（pRb）及其相关蛋白p107和p130在控制哺乳动物细胞分裂周期中起关键作用，我们研究了原代B淋巴细胞经EBV永生化后这些蛋白的表达和磷酸化状态。在本报告中，我们表明EBV会促使pRb发生过度磷酸化。这是通过一种策略实现的，该策略涉及信号转导通路中几个通常调节pRb磷酸化状态的组分的表达改变，包括一些细胞周期蛋白和细胞周期蛋白依赖性激酶的上调以及细胞周期蛋白依赖性激酶抑制剂子集的下调。最终结果是形成能够磷酸化并使pRb失活的活性细胞周期蛋白依赖性激酶复合物。此处呈现的结果表明，激活正常的信号转导通路是EBV驱动细胞增殖所采用策略的一个重要组成部分。
