Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, PR China.
Cell Cycle. 2012 Sep 15;11(18):3463-71. doi: 10.4161/cc.21770. Epub 2012 Aug 23.
The essential function of eIF4E-binding protein 1 (4E-BP1) in translation initiation has been well established; however, the role of 4E-BP1 in normal cell cycle progression is coming to attention. Here, we revealed the role of 4E-BP1 on mitotic regulation and chromosomal DNA dynamics during mitosis. First, we have observed the co-localization of the phosphorylated 4E-BP1 at T37/46 with Polo-like kinase 1 (PLK1) at the centrosomes during. Depression of 4E-BP1 by small interfering RNA in HepG2 or HeLa cells resulted in an increased outcome of polyploidy and aberrant mitosis, including chromosomal DNA misaligned and multi-polar spindles or multiple centrosomes. We observed that 4E-BP1 interacted with PLK1 directly in vitro and in vivo in mitotic cells, and the C-terminal aa 77-118 of 4E-BP1 mediates its interaction with PLK1. PLK1 can phosphorylate 4E-BP1 in vitro. Furthermore, the depletion of 4E-BP1 sensitized HepG2 and HeLa cells to the microtubule disruption agent paclitaxel. These results demonstrate that 4E-BP1, beyond its role in translation regulation, can function as a regulator of mitosis via interacting with PLK1, and possibly plays a role in genomic stability maintaining.
真核起始因子 4E 结合蛋白 1（4E-BP1）在翻译起始中的基本功能已得到充分证实；然而，4E-BP1 在正常细胞周期进展中的作用正受到关注。在这里，我们揭示了 4E-BP1 在有丝分裂调节和有丝分裂过程中染色体 DNA 动力学中的作用。首先，我们观察到磷酸化的 4E-BP1 在 T37/46 处与中心体中的 Polo 样激酶 1（PLK1）共定位。在 HepG2 或 HeLa 细胞中通过小干扰 RNA 抑制 4E-BP1 会导致多倍体和异常有丝分裂的增加，包括染色体 DNA 不对齐和多极纺锤体或多个中心体。我们观察到 4E-BP1 在有丝分裂细胞中体外和体内直接与 PLK1 相互作用，并且 4E-BP1 的 C 末端 aa77-118 介导其与 PLK1 的相互作用。PLK1 可以在体外磷酸化 4E-BP1。此外，4E-BP1 的耗竭使 HepG2 和 HeLa 细胞对微管破坏剂紫杉醇敏感。这些结果表明，4E-BP1 除了在翻译调节中的作用外，还可以通过与 PLK1 相互作用作为有丝分裂的调节剂发挥作用，并可能在维持基因组稳定性中发挥作用。
