Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state.
Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state.
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DOI：
10.7554/elife.03915
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发表时间：
2014-11-07
期刊：
影响因子：
7.7
通讯作者：
Burge CB
中科院分区：
文献类型：
--
作者：
Katz Y;Li F;Lambert NJ;Sokol ES;Tam WL;Cheng AW;Airoldi EM;Lengner CJ;Gupta PB;Yu Z;Jaenisch R;Burge CB
RNA结合蛋白的保守Musashi（Msi）家族在干/祖细胞和癌细胞中表达，但通常不存在于分化细胞中，这与细胞状态调节中的作用一致。我们发现Msi基因很少突变，但在人类癌症中经常过度表达，并与上皮细胞状态有关。使用核糖体分析和RNA-seq分析，我们发现Msi蛋白调节与上皮细胞生物学和上皮-间充质转化（EMT）有关的基因的翻译，并促进上皮剪接模式。Msi蛋白的过表达抑制了Jagged 1的翻译，这是EMT所需的因子，并抑制了细胞培养和体内乳腺中的EMT。上皮癌细胞中Msis的敲低促进上皮身份的丧失。我们的研究结果表明，哺乳动物Msi蛋白有助于神经和乳腺细胞类型中的上皮基因表达程序。http://dx.doi.org/10.7554/eLife.03915.001所有生物都是从单个细胞开始生命的，但许多生物体发展成为不同的、专门的细胞的集合。生物体中的大多数细胞只能分裂以产生更多的相同类型的细胞;然而，干细胞不同，因为它们可以“分化”并发育成几种不同的细胞类型。胚胎发育的关键一步是上皮细胞向间质细胞的转化，在这一过程中，上皮细胞一种通常排列在体表和体腔内的细胞类型开始从它所在的组织中爬出并开始分化。这种转变也允许癌细胞离开肿瘤并在身体周围扩散，这一过程称为转移。在哺乳动物中，两种名为Musashi 1和Musashi 2的蛋白质在干细胞和脑癌中大量存在，但很少在专门的组织和细胞中发现。Katz，Li等人现在发现Musashi蛋白也经常在人类乳腺、肺和前列腺肿瘤中过表达。此外，Musashi蛋白在已经完成上皮向间充质转化的细胞中的丰度要低得多。当Katz，Li等人人为地减少乳腺癌细胞中Musashi蛋白的量时，细胞迁移和分散，好像变成了间充质细胞。此外，许多通常用于上皮细胞的基因被关闭。相比之下，人为增加Musashi蛋白质的水平会阻止间充质细胞的运动，并导致上皮细胞中使用的基因水平增加，就好像它们正在恢复为上皮细胞一样。因此，似乎Musashi蛋白阻止上皮细胞发展间充质性质。Katz，Li等人通过研究小鼠的神经细胞和乳腺细胞，研究了Musashi蛋白质在分子水平上的作用。这表明，Musashi蛋白通过结合RNA分子的末端来控制导致上皮向间充质转化的步骤，RNA分子包括制造某些蛋白质的指令。这影响了这些蛋白质从RNA分子中产生的频率。Katz，Li等人认为Musashi蛋白可能同样控制许多其他组织中祖细胞和干细胞的行为;然而，需要进一步的研究来证实这一点。DOI：http://dx.doi.org/10.7554/eLife.03915.002网站
The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types. DOI: http://dx.doi.org/10.7554/eLife.03915.001 All living things start life as a single cell, but many organisms develop into a collection of different, specialized cells. Most of the cells in an organism can only divide to make more of the same type of cell; however, stem cells are different because they can ‘differentiate’ and develop into several different cell types. A key step in the development of an embryo is called the epithelial-to-mesenchymal transition, in which an epithelial cell—a cell type that normally lines body surfaces and cavities—begins to crawl away from the tissue it is in and starts to differentiate. This transition also allows cancer cells to leave tumors and spread around the body, in a process known as metastasis. In mammals, two proteins called Musashi1 and Musashi2 are abundant in stem cells and brain cancers, but are rarely found in specialized tissues and cells. Katz, Li et al. now find that the Musashi proteins are also often overexpressed in human breast, lung, and prostate tumors. In addition, Musashi proteins are much less abundant in cells that have completed an epithelial-to-mesenchymal transition. When Katz, Li et al. artificially reduced the amounts of Musashi proteins in breast cancer cells, the cells migrated and dispersed, as if becoming mesenchymal cells. Furthermore, many of the genes normally used in epithelial cells were switched off. In comparison, artificially increasing the levels of Musashi proteins halted the movement of mesenchymal cells and led to increased levels of genes used in epithelial cells, as if they were reverting to epithelial cells. Therefore, it appears that the Musashi proteins prevent epithelial cells from developing mesenchymal properties. Katz, Li et al. investigated how Musashi proteins work at the molecular level by studying neural and mammary cells in mice. This revealed that Musashi proteins control the steps that lead to the epithelial-to-mesenchymal transition by binding to the tail end of the RNA molecules that include the instructions to make certain proteins. This affects how often these proteins can be made from the RNA molecules. Katz, Li et al. suggest that Musashi proteins may similarly control the behavior of progenitor and stem cells in many other tissues as well; however, further study is needed to confirm this. DOI: http://dx.doi.org/10.7554/eLife.03915.002
影响因子：
3.7
作者：
Ber S;Lee C;Voiculescu O;Surani MA
通讯作者：
Surani MA