Targeting nuclear import and export in hematological malignancies.
Targeting nuclear import and export in hematological malignancies.
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DOI：
10.1038/s41375-020-0958-y
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发表时间：
2020-11
期刊：
影响因子：
11.4
通讯作者：
Schimmer AD
中科院分区：
文献类型：
--
作者：
Nachmias B;Schimmer AD
蛋白质跨核膜的运输是一个高度调节的过程，对细胞功能至关重要。这种转运是由核转运蛋白家族的成员主动介导的，根据转运的方向，核转运蛋白家族被称为输入蛋白或输出蛋白。这些蛋白质通过其货物的异常定位在肿瘤发生中发挥积极作用，所述货物包括癌基因、肿瘤抑制基因和关键信号转导通路的介质。在许多恶性肿瘤中报告了importins和exportins的过表达，其影响细胞生长和活力、分化、耐药性和肿瘤微环境。鉴于其在肿瘤和通路中的广泛意义，人们正在努力开发特异性抑制剂作为新型抗癌治疗剂。selinexor是一种特异性的exportin-1（XPO 1）抑制剂，已被批准用于临床。本文将重点介绍输入蛋白和输出蛋白在血液系统恶性肿瘤中的作用。我们将讨论目前的临床前和临床数据的importins和exportins，并证明我们如何不断增长的了解他们的功能，确定了新的治疗目标。
The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.
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