The transcriptional response to tumorigenic polarity loss in Drosophila.
The transcriptional response to tumorigenic polarity loss in Drosophila.
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DOI：
10.7554/elife.03189
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发表时间：
2015-02-26
期刊：
影响因子：
7.7
通讯作者：
Bilder D
中科院分区：
文献类型：
--
作者：
Bunker BD;Nellimoottil TT;Boileau RM;Classen AK;Bilder D
极性的丧失与上皮癌的进展相关，但质膜的错误组织如何驱动致癌转录事件仍不清楚。果蝇Scribble（Scrib）模块的极性调节剂是有效的肿瘤抑制剂，并提供了一个模型的机制调查。Scrib突变肿瘤的RNA分析揭示了肿瘤形成的多种特征，包括代谢改变和去分化。其中最突出的是促进肿瘤过度生长的精氨酸样未配对（Upd）配体的上调。我们在upd 3中发现了一个极性响应增强子，该增强子通过JNK依赖的Fos和aPKC介导的Yki转录以一致的方式激活。这种增强子和Scrib突变体的过度生长通常也对Polycomb组（PcG）的活性敏感，这表明PcG在极性丧失后的衰减增强了JNK和Yki激活的选择靶标。我们的研究结果将上皮组织与控制组织修复程序的信号传导和表观遗传调节因子联系起来，并深入了解上皮极性为何具有肿瘤抑制作用。DOI：http://dx.doi.org/10.7554/eLife.03189.001我们体内的腔和器官排列着上皮细胞，它们相互连接形成连续的屏障。这些细胞具有高度极化的结构，其中在细胞的顶部和底部发现不同的组分。在果蝇和大多数其他动物中，三个被称为Scribble模块的基因控制着上皮细胞的极性。如果这些基因有缺陷，细胞就会失去极性，打破上皮屏障，迅速生长形成肿瘤。大多数由上皮细胞形成的恶性肿瘤已经失去了正常的细胞极性，因此了解上皮细胞的组织和生长是如何联系在一起的是一个关键问题。目前尚不清楚细胞极性的丧失如何驱动肿瘤形成。在这里，掩体等人使用一种称为RNA测序的技术来研究在Scribble模块中具有突变的肿瘤细胞中基因的表达。肿瘤细胞中的数百个基因的表达水平与正常果蝇细胞中的表达水平不同。其中之一是一种叫做upd 3的基因，它在肿瘤细胞中的表达比正常细胞高得多。这种基因激活一种信号通路--JAK/STAT通路--在许多动物中促进细胞生长和分裂。掩体等人发现，通过实验降低JAK/STAT通路的活性，可以减少失去正常极性的肿瘤细胞的生长。进一步的实验表明，破坏上皮细胞层会激活另外两条信号通路，当细胞极性丧失时，这两条信号通路共同作用，开启upd 3基因。属于Polycomb组的蛋白质还通过改变遗传物质在细胞中的包装方式来控制upd 3和其他参与细胞生长的基因的表达。这种反应和对组织损伤的反应之间的相似性表明，极性的丧失通过不可阻挡的伤口愈合反应驱动肿瘤形成。因此，掩体et al.的发现将上皮肿瘤的形成与控制受损组织修复的信号通路联系起来。DOI：http://dx.doi.org/10.7554/eLife.03189.002网站
Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive. DOI: http://dx.doi.org/10.7554/eLife.03189.001 The cavities and organs within our body are lined with epithelial cells, which connect to each other to form continuous barriers. These cells have a highly polarized structure in which different components are found at the top and bottom of cells. In the fruit fly and most other animals, three genes known as the Scribble module control the polarity of epithelial cells. If these genes are faulty, the cells lose their polarity, break the epithelial barrier, and grow rapidly to form a tumor. Most malignant tumors that form from epithelial cells have lost normal cell polarity, so understanding how the organization and growth of epithelial cells are linked is a critical question. It is not clear how the loss of cell polarity can drive tumor formation. Here, Bunker et al. used a technique called RNA sequencing to study the expression of genes in tumor cells that have mutations in the Scribble module. Hundreds of genes in the tumor cells had different levels of expression from the levels seen in normal fly cells. One of these is a gene called upd3, which was expressed much more highly in tumor cells than in normal cells. This gene activates a signaling pathway—called the JAK/STAT pathway—that promotes cell growth and division in many animals. Bunker et al. found that experimentally lowering the activity of the JAK/STAT pathway reduced the growth of the tumor cells that had lost normal polarity. Further experiments show that disrupting the layer of epithelial cells activates two other signaling pathways that work together to switch on the upd3 gene when cell polarity is lost. Proteins belonging to the Polycomb Group also control the expression of upd3 and other genes involved in cell growth by altering how genetic material is packaged in cells. The similarities between this response and the response to tissue damage suggest that the loss of polarity drives tumor formation through an unstoppable wound-healing reaction. Therefore, Bunker et al.'s findings link the formation of epithelial tumors to the signaling pathways that control the repair of damaged tissues. DOI: http://dx.doi.org/10.7554/eLife.03189.002