Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis
Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis
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DOI：
10.1128/mcb.23.24.8992-9002.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Borden, KLB
中科院分区：
文献类型：
--
作者：
Topisirovic, I;Guzman, ML;Borden, KLB
真核生物翻译起始因子4 E（eIF 4 E）既是一个关键的翻译因子，又是一个核质转运的启动子。传统上，其体内转化能力归因于其在细胞质中的翻译起始中的作用。在这里，我们证明了升高的eIF 4 E阻碍粒细胞和单核细胞分化。我们随后的诱变研究表明，这种阻断是eIF 4 E依赖性mRNA转运失调的结果。这些研究表明eIF 4 E的RNA转运功能可能有助于白血病的发生。我们扩展了我们的研究，以提供eIF 4 E的核转运功能有助于人类恶性肿瘤的第一个证据，特别是在急性和慢性髓性白血病患者的子集。我们观察到eIF 4 E依赖性细胞周期蛋白D1 mRNA转运的增加和细胞周期蛋白D1蛋白水平的伴随增加。eIF 4 E的异常核功能是由于异常大的eIF 4 E体和富含脯氨酸的同源结构域PRH的调节丧失。我们开发了一种新的工具来调节这种运输活动。NF-κ B的阻遏物IkappaB的引入导致eIF 4 E的抑制、PRH的升高、eIF 4 E核体的重组以及随后的eIF 4 E依赖性mRNA转运的下调。因此，我们的研究结果表明，eIF 4 E的这种核功能可以通过促进生长和阻碍分化来促进白血病的发生。
The eukaryotic translation initiation factor 4E (eIF4E) acts as both a key translation factor and as a promoter of nucleocytoplasmic transport of specific transcripts. Traditionally, its transformation capacity in vivo is attributed to its role in translation initiation in the cytoplasm. Here, we demonstrate that elevated eIF4E impedes granulocytic and monocytic differentiation. Our subsequent mutagenesis studies indicate that this block is a result of dysregulated eIF4E-dependent mRNA transport. These studies indicate that the RNA transport function of eIF4E could contribute to leukemogenesis. We extended our studies to provide the first evidence that the nuclear transport function of eIF4E contributes to human malignancy, specifically in a subset of acute and chronic myelogenous leukemia patients. We observe an increase in eIF4E-dependent cyclin D1 mRNA transport and a concomitant increase in cyclin D1 protein levels. The aberrant nuclear function of eIF4E is due to abnormally large eIF4E bodies and the loss of regulation by the proline-rich homeodomain PRH. We developed a novel tool to modulate this transport activity. The introduction of IkappaB, the repressor of NF-kappaB, leads to suppression of eIF4E, elevation of PRH, reorganization of eIF4E nuclear bodies, and subsequent downregulation of eIF4E-dependent mRNA transport. Thus, our findings indicate that this nuclear function of eIF4E can contribute to leukemogenesis by promoting growth and by impeding differentiation.