文章：

核转运与癌症：从机制到干预

Nuclear transport and cancer: from mechanism to intervention

原文发布日期：2004-02-01

DOI: 10.1038/nrc1274

类型: Review Article

开放获取: 否

要点：

1. Nuclear-cytoplasmic transport of oncogenes and tumour suppressors is disrupted in cancer cells. Transport can be regulated by modification of the cargo, at the level of the transport machinery or at the level of the nuclear-pore complex (NPC). Modifying the nuclearcytoplasmic transport activity might block tumorigenesis.
2. Karyopherin-α and karyopherin-β transport cargoes that contain nuclear localization signals (NLSs) into the nucleus through the NPC. CRM1 is the transport receptor that exports nuclear export signal (NES)-containing proteins out of the nucleus.
3. The RanGTP/GDP gradient across the nuclear envelope promotes the direction of transport.
4. Hyper-active forms of AKT can lead to the mislocalization and therefore inactivation of proteins such as the FOXO transcription factors and p27 cell-cycle inhibitor.
5. Wild-type p53 is mislocalized to the cytoplasm in many cancers, possibly due, in part, to association with the cytoplasmic anchor protein PARC.
6. Stable, nuclear β-catenin is a hallmark of colon cancer cells. Experiments have implicated inefficient export by a mutant form of APC as a possible cause of nuclear β-catenin.
7. Altered expression of nuclear transport factors, such as karyopherins and nucleoporins, have been implicated in tumorigenesis.
8. Leptomycin B is a potent and specific covalent inhibitor of CRM1 and can sequester proteins in the nucleus.
9. Visual, high-throughput and high-content small-molecule screens for compounds that re-direct mislocalized proteins to the correct cellular compartment might reveal novel anticancer agents.

要点翻译：

1. 癌基因和肿瘤抑制因子的核质运输在癌细胞中发生紊乱。运输过程可通过修饰货物、在运输机制层面或在核孔复合体（NPC）层面进行调控。改变核质运输活性可能阻断肿瘤发生。
2. 核转运蛋白α和核转运蛋白β通过核孔复合体将含有核定位信号（NLS）的货物转运至细胞核。CRM1是负责将含有核输出信号（NES）的蛋白质从细胞核输出的转运受体。
3. RanGTP/GDP跨核被膜的梯度促进运输方向的选择。
4. AKT的过度活化形式可导致蛋白质错误定位进而失活，如FOXO转录因子和p27细胞周期抑制剂。
5. 在许多癌症中，野生型p53错误定位于细胞质，部分原因可能与细胞质锚定蛋白PARC的结合有关。
6. 稳定的核β-连环蛋白是结肠癌细胞的标志。实验表明APC突变体形式的低效输出可能是核β-连环蛋白积累的原因。
7. 核转运因子（如核转运蛋白和核孔蛋白）表达改变与肿瘤发生密切相关。
8. 勒铂霉素B是CRM1的高效特异性共价抑制剂，能将蛋白质滞留于细胞核。
9. 针对能重新定向错误定位蛋白质至正确细胞区室的化合物开展可视化、高通量和高内涵小分子筛选，可能发现新型抗癌药物。

英文摘要：

Nuclear-cytoplasmic transport, which occurs through special structures called nuclear pores, is an important aspect of normal cell function, and defects in this process have been detected in many different types of cancer cells. These defects can occur in the signal-transduction pathways that regulate the transfer of factors such as p53 and β-catenin in and out of the nucleus, or in the general nuclear import and export machinery itself. In some cases, nuclear transport factors are overproduced, whereas in others, chromosomal translocations disrupt the structural proteins that make up the nuclear pore, leading to cell transformation. How does disruption of nuclear-cytoplasmic transport promote transformation, and is this process a viable therapeutic target?

摘要翻译： 

核-质运输通过称为核孔的特殊结构进行，是正常细胞功能的重要方面；该过程的缺陷已在多种癌细胞中被发现。这些缺陷可发生在调控p53、β-连环蛋白等因子进出核的信号转导通路，也可发生在通用的核输入/输出机制本身。某些情况下，核运输因子被过度产生；另一些情况下，染色体易位破坏了构成核孔的结构蛋白，导致细胞转化。核-质运输的破坏如何促进转化？这一过程是否可作为可行的治疗靶点？

原文链接：

Nuclear transport and cancer: from mechanism to intervention