Molecular mechanism for cell-cell adhesion in canceration and metastasis

癌变和转移中细胞粘附的分子机制

• 批准号: 12219210
• 负责人: TSUKITA Shoichiro
• 金额: $ 284.1万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219210/
• 关键词: cell-cell adhesion; tight junction; claudin; occludin; ERM proteins; epidermal barrier; knockout mouse; cell proliferation; Snail; ZO-1; ZO-2; がん; 上皮間葉転換; 転移浸潤; GFP; ドラッグデリバリー; ノックアウト; 上皮細胞; 血液脳関門; メルリン; MUPP1; PDZドメイン; 大腸癌; ラディキシン

More than 90% of malignant tumors are derived from the epithelium. Thus, in this project, we focused on the analyses of tight junctions and ERM proteins to clarify the nature of the. epithelium. Major results are as follows:1. Claudin-1-deficient mice were generated. Their epidermal barrier was affected, and the proliferation of epidermal cells appeared to be abnormal.2. Claudin-5-deficient mice were generated. Their blood-brain barrier was affected in a size-dependent manner. This finding was intriguing from the viewpoint of drug deliver to the brain tumors.3. The dynamic behavior of claudin-based tight junction strands was successfully observed in live cells. Their behavior was more dynamic than ever expected.4. Snail, a transcription factor, plays a key role in the epithelial-mesenchymal transition, which is important in the metastasis of cancer cells. We found that Snail completely repressed the transcription of occludin and claudins through its direct binding to the E-boxes of the promoter regions of these genes.5. Claudin-1 was shown to be overexpressed in human colon cancer (in collaboration with Prof. Nakamura's group).6. We established the system, in which a certain gene can be double-knocked out in cultured epithelial cells. With this system, an epithelial cell line lacking the expression of ZO-1 and ZO-2 was established.7. The structure of the gene product of NF2, an ERM-like tumor suppressor gene, was clarified by X-ray diffraction analyses (in collaboration with Prof.Hakozaki's group).

超过90％的恶性肿瘤来自上皮。因此，在这个项目中，我们专注于对紧密连接和ERM蛋白的分析，以阐明其性质。上皮。主要结果如下：1。产生了Claudin-1缺陷小鼠。它们的表皮屏障受到影响，表皮细胞的增殖似乎异常。2。产生了Claudin-5缺陷小鼠。它们的血脑屏障以大小依赖的方式受到影响。从传递给脑肿瘤的药物的角度来看，这一发现吸引了3。在活细胞中成功观察到了基于克劳丁的紧密连接链的动态行为。他们的行为比以往任何时候都更具动态。4。蜗牛是一种转录因子，在上皮间质转变中起关键作用，这在癌细胞的转移中很重要。我们发现，蜗牛通过直接结合了这些基因的启动子区域的电子盒，完全抑制了occludin和claudins的转录。5。 Claudin-1被证明在人类结肠癌中过表达（与中村教授的小组合作）。6。我们建立了一个系统，其中某个基因可以在培养的上皮细胞中双重敲除。使用该系统，建立了缺乏ZO-1和ZO-2表达的上皮细胞系。7。通过X射线衍射分析（与Hakozaki的组合作）阐明了NF2的基因产物的结构。

项目成果

CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex.

• DOI: 10.1083/jcb.200405094
• 发表时间: 2005-01-03
• 期刊: The Journal of cell biology
• 作者: Mimori-Kiyosue Y;Grigoriev I;Lansbergen G;Sasaki H;Matsui C;Severin F;Galjart N;Grosveld F;Vorobjev I;Tsukita S;Akhmanova A
• 通讯作者: Akhmanova A

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Matsuda, M. et al.: "A peculiar internalization of claudins, tight junction-specific adhesion molecules, during the intercellular movement of epithelial cells"J.Cell Sci.. 印刷中. (2004)

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