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).

90%以上的恶性肿瘤来源于上皮细胞。因此，在这个项目中，我们重点分析紧密连接和 ERM 蛋白，以阐明其本质。上皮。主要研究结果如下： 1．产生了 Claudin-1 缺陷小鼠。表皮屏障受到影响，表皮细胞增殖异常。2．产生了 Claudin-5 缺陷小鼠。他们的血脑屏障受到大小依赖性的影响。从药物递送至脑肿瘤的角度来看，这一发现很有趣。3．在活细胞中成功观察到基于紧密连接蛋白的紧密连接链的动态行为。他们的行为比以往预期的更加活跃。4。 Snail 是一种转录因子，在上皮-间质转化中发挥关键作用，这对癌细胞的转移至关重要。我们发现Snail通过直接结合occludin和claudin基因启动子区的E盒来完全抑制这些基因的转录。5．研究表明，Claudin-1 在人类结肠癌中过度表达（与 Nakamura 教授的团队合作）。6．我们建立了一个系统，可以在培养的上皮细胞中双敲除某个基因。利用该系统，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教授小组合作）阐明了NF2（一种ERM样肿瘤抑制基因）的基因产物的结构。

项目成果

Sakaki, H. et al.: "Dynamic behavior of paired claudin strands within apposing plasma membranes"Pro.Natl.Acad.Sci.USA. 100. 3971-3976 (2003)

Sakaki, H. 等人：“并列质膜内成对密蛋白链的动态行为”Pro.Natl.Acad.Sci.USA。

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)

Matsuda, M. 等人：“上皮细胞细胞间运动过程中紧密连接特异性粘附分子的特殊内化”J.Cell Sci.. 出版中（2004 年）。

Nitta, T.et al.: "Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice"J.Cell.Biol.. 161. 653-660 (2003)

Nitta，T.等人：“claudin-5 缺陷小鼠中血脑屏障的尺寸选择性松弛”J.Cell.Biol.. 161. 653-660 (2003)

Furuse, M.: "Claudin-based tight junctions are crucial for the mammalian epidermal barrier : A lesson from claudin-deficient mice"Journal of Cell Biology. (印刷中). (2002)

Furuse, M.：“基于紧密连接蛋白的紧密连接对于哺乳动物表皮屏障至关重要：来自紧密连接蛋白缺陷小鼠的教训”《细胞生物学杂志》（2002 年出版）。

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