Analysis of cell adhesion and polarity formation by a novel tumor suppressor protein TSLC1 and its related molecules

新型抑癌蛋白TSLC1及其相关分子对细胞粘附和极性形成的分析

• 批准号: 15590262
• 负责人: MURAKAMI Yoshinori
• 金额: $ 2.18万
• 依托单位: National Cancer Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590262/
• 关键词: TSLC1; Proteins 4.1; Membrane assopciated guanylate kinase; Cel adhesion; Epithelial like cell structure; RNAi; 膜結合性アデニレート・シクラーゼ; がん抑制遺伝子; MPP3; 細胞極性; DLG

Morphological transformation is a fundamental feature of malignant cancer cells. The tumor suppressor, TSLC1/IGSF4, is involved in cell adhesion and preferentially inactivated in invasive cancer. We have previously shown that TSLC1 associates with an actin-binding protein, DAL-1/4.1B, and a scaffold protein, membrane protein palmitoylated 3(MPP3). Here, we identified MPP1/p55 and MPP2/DLG2 as additional cytoplasmic proteins binding to TSLC1 and investigated the roles of the TSLC1 cascade in epithelial cell morphology and its malignant transformation. MPP1, MPP2, and MPP3 interacted directly with DAL-1, forming a tripartite complex with TSLC1. Whereas these complexes localized along the cell membranes in confluent HEK293 cells, only MPP2, but not MPP1 or MPP3, was recruited to the TSLC1-DAL-1 complex in the early process of cell adhesion. When the TSLC1 function was abrogated by RNAi, HEK293 losed epithelial-like structure and showed flat morphology with immature cell adhesion. Furthermore, DAL-1 and MPP2, as well as E-cadherin and ZO-1, were mislocalized from the membrane. Loss of TSLC1 was also correlated with the transformed phenotype of lung cancer cells. These findings suggest that TSLC1 is involved in the formation of epithelial-like cell structure with DAL-1 and MPPs, while loss of its function could cause morphological transformation of cancer cells.

形态转化是恶性肿瘤细胞的一个基本特征。肿瘤抑制因子TSLC1/IGSF4参与细胞黏附，在浸润性癌中优先失活。我们先前已经证明TSLC1与肌动蛋白结合蛋白DAL-1/4.1B和支架蛋白Palmitoylated 3(MPP3)相关。在这里，我们确定MPP1/P55和MPP2/DLG2是与TSLC1结合的额外的细胞质蛋白，并研究了TSLC1级联在上皮细胞形态及其恶性转化中的作用。MPP1、MPP2、MPP3与DAL-1直接相互作用，与TSLC1形成三元复合体。而在融合的HEK293细胞中，这些复合体位于细胞膜上，在细胞黏附的早期，只有MPP2，而不是MPP1或MPP3被招募到TSLC1-DAL-1复合体中。当TSLC1功能被RNAi取消后，HEK293细胞失去上皮样结构，形态扁平，细胞黏附不成熟。此外，DAL-1和MPP2以及E-钙粘蛋白和ZO-1也错误地定位于细胞膜。TSLC1的缺失也与肺癌细胞的转化表型有关。这些发现表明，TSLC1参与了DAL-1和MPPS上皮样细胞结构的形成，而其功能的丧失可能导致癌细胞的形态转化。

项目成果

Ito, T., Shimada, Y., Murakami, Y., Imamura, M.et al.: "Involvement of TSLC1 in progression of esophageal squamous cell carcinoma."Cancer Research. 63. 6320-6326 (2003)

Ito, T.、Shimada, Y.、Murakami, Y.、Imamura, M.等人：“TSLC1 参与食管鳞状细胞癌的进展。”癌症研究。

Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3.

• DOI: 10.3892/or.12.1.47
• 发表时间: 2004-07
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: M. Saino;T. Maruyama;T. Sekiya;T. Kayama;Y. Murakami

Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg

• DOI: 10.1038/sj.onc.1206744
• 发表时间: 2003-09-18
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Fukuhara, H;Masvuda, M;Murakami, Y
• 通讯作者: Murakami, Y

The cytoplasmic domain is critical to the tumour suppressor activity of TSLC1 in non-small cell lung cancer.

胞质结构域对于 TSLC1 在非小细胞肺癌中的肿瘤抑制活性至关重要。

• 发表时间: 2003
• 期刊: Cancer Res. 63
• 作者: Mao;X.;Seidlitz;E.;Ghosh;K.;Murakami;Y.;Ghosh;H.P.
• 通讯作者: H.P.

Fukami, T., Murakami, Y.et al.: "Isolation of the mouse Tsll1 and Tsll2 genes, orthologues of the human TSLC1-like genes 1 and 2 (TSLL1 and TSLL2)."Gene. 323. 11-18 (2003)

Fukami, T., Murakami, Y.等人：“小鼠 Tsll1 和 Tsll2 基因的分离，它们是人类 TSLC1 样基因 1 和 2（TSLL1 和 TSLL2）的直系同源物。”基因。