Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells
Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells
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DOI：
10.1038/sj.onc.1208962
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发表时间：
2005-12-15
期刊：
影响因子：
8
通讯作者：
Mortin, MA
中科院分区：
文献类型：
--
作者：
Bi, XL;Jones, T;Mortin, MA
我们以前表明，果蝇DNA结合同源结构域的普洛斯彼罗包括一个28个氨基酸序列（HDA），作为一个核输出信号的功能。我们在这里描述了一种我们命名为Caliban的蛋白质的鉴定，它可以直接与HDA相互作用。Caliban与人Sdccag 1同源，后者与结肠癌和肺癌有关。在这里，我们表明，Caliban和Sdccag 1是在苍蝇和人类细胞的核输出介质，干扰RNA废除出口EYFP-HDA在正常苍蝇和人类肺细胞。由于羧基末端结合HDA，氨基末端本身作为内斯起作用，其直接结合内斯受体Exportin，因此Caliban起双向介体核输出的作用。最后，虽然非癌性肺细胞具有功能性Sdccag 1，但五种人肺癌细胞系没有，即使Exportin仍然在这些细胞中起作用。在这些人肺癌细胞中表达苍蝇Caliban恢复EYFP-HDA核输出，降低细胞在软琼脂上形成集落的能力，并降低细胞侵袭力。我们认为，Sdccag 1失活有助于人肺癌细胞的转化状态，并认为Caliban应被视为用于肺癌基因治疗的候选人。
We previously showed that the Drosophila DNA binding homeodomain of Prospero included a 28 amino-acid sequence (HDA) that functions as a nuclear export signal. We describe here the identification of a protein we named Caliban, which can directly interact with the HDA. Caliban is homologous to human Sdccag1, which has been implicated in colon and lung cancer. Here we show that Caliban and Sdccag1 are mediators of nuclear export in fly and human cells, as interference RNA abrogates export of EYFP-HDA in normal fly and human lung cells. Caliban functions as a bipartite mediator nuclear export as the carboxy terminus binds HDA and the amino terminus itself functions as an NES, which directly binds the NES receptor Exportin. Finally, while non-cancerous lung cells have functional Sdccag1, five human lung carcinoma cell lines do not, even though Exportin still functions in these cells. Expression of fly Caliban in these human lung cancer cells restores EYFP-HDA nuclear export, reduces a cell's ability to form colonies on soft agar and reduces cell invasiveness. We suggest that Sdccag1 inactivation contributes to the transformed state of human lung cancer cells and that Caliban should be considered a candidate for use in lung cancer gene therapy.