Guy C T, Zhou W, Kaufman S, Robinson M O
Amgen, Inc., Thousand Oaks, California 91320, USA.
Mol Cell Biol. 1996 Feb;16(2):685-93. doi: 10.1128/MCB.16.2.685.
The transcription factor E2F-1 plays a central role in the cell cycle through its ability to activate genes involved in cell division. E2F-1 activity is regulated by a number of proteins, including the retinoblastoma susceptibility gene product, cyclin-dependent kinases, and their inhibitors, proteins that have been implicated in the control of certain developmental processes. To investigate a potential role of E2F-1 in differentiation, we assayed the ability of megakaryocytes to form platelets in an in vivo transgenic model. E2F-1 expression in megakaryocytes blocked differentiation during maturation, resulting in severe thrombocytopenia. Ultrastructural analysis of megakaryocytes revealed abnormal development characterized by hyperdemarcation of cytoplasmic membranes and reduced numbers of alpha granules. Administration of megakaryocyte growth and development factor or interleukin 6 could not overcome the differentiation block. Additionally, E2F-1 caused massive megakaryocyte accumulation in both normal and ectopic sites, first evident in E15 embryonic liver. Furthermore, significant apoptosis was observed in transgenic megakaryocytes. These data indicate that E2F-1 can prevent terminal differentiation, probably through its cell cycle-stimulatory activity.
转录因子E2F-1通过激活参与细胞分裂的基因，在细胞周期中发挥核心作用。E2F-1的活性受多种蛋白质调控，包括视网膜母细胞瘤易感基因产物、细胞周期蛋白依赖性激酶及其抑制剂，这些蛋白质与某些发育过程的控制有关。为了研究E2F-1在分化中的潜在作用，我们在体内转基因模型中检测了巨核细胞形成血小板的能力。巨核细胞中E2F-1的表达在成熟过程中阻断了分化，导致严重的血小板减少症。巨核细胞的超微结构分析显示发育异常，其特征为细胞质膜过度分割和α颗粒数量减少。给予巨核细胞生长和发育因子或白细胞介素6无法克服分化障碍。此外，E2F-1在正常和异位部位均导致大量巨核细胞积聚，最早在E15胚胎肝脏中明显可见。此外，在转基因巨核细胞中观察到明显的凋亡。这些数据表明，E2F-1可能通过其细胞周期刺激活性阻止终末分化。
