Bitterman Peter B, Polunovsky Vitaly A
Department of Medicine, University of Minnesota, 420 Delaware Street S.E., MMC 276, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, 420 Delaware Street S.E., MMC 276, Minneapolis, MN 55455, USA.
Biochim Biophys Acta. 2015 Jul;1849(7):774-80. doi: 10.1016/j.bbagrm.2014.09.007. Epub 2014 Sep 28.
Mitogen activated translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when deregulated and overexpressed. It remains unknown, how activated eIF4E directs such distinct biological outputs. Our experimental data provide evidence that distinct threshold levels of eIF4E govern its biological output in lactating mammary glands and that eIF4E overexpression in the context of cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints caused by hyperproliferative oncogenic stimuli. These findings point at the cellular level of eIF4E as an important sensor for normal or pro-neoplastic propagation of cells. Here, we describe a model that links the pro-neoplastic function of eIF4F to its ability to disable oncogene-activated tumor surveillance programs; and propose a novel therapeutic strategy for cancer prevention based upon targeting aberrant eIF4E with safe doses of small-molecule antagonists to ensure the maintenance of eIF4E levels below the pro-neoplastic threshold. This article is part of a Special Issue entitled: Translation and Cancer.
有丝分裂原激活的翻译起始因子eIF4E介导正常细胞增殖，但在失调和过表达时会诱导肿瘤发生。目前尚不清楚，激活的eIF4E是如何引导这种截然不同的生物学结果的。我们的实验数据表明，eIF4E的不同阈值水平决定了其在泌乳乳腺中的生物学结果，并且在细胞群体扩张的情况下，eIF4E过表达可通过使细胞逃避由过度增殖的致癌刺激引起的DNA损伤检查点来启动恶性转化。这些发现表明，在细胞水平上，eIF4E是细胞正常或肿瘤前增殖的重要传感器。在此，我们描述了一个模型，该模型将eIF4F的肿瘤前功能与其禁用癌基因激活的肿瘤监测程序的能力联系起来；并基于用安全剂量的小分子拮抗剂靶向异常的eIF4E以确保将eIF4E水平维持在肿瘤前阈值以下，提出了一种新的癌症预防治疗策略。本文是名为“翻译与癌症”的特刊的一部分。
