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ELUDICATION OF ASSOCIATION AND SIGNAL TRANSDUCTION PATHWAY BETWEEN BETA-KATENIN AND GROWTH FACTOR RECEPTOR AT THE CANCER INVASION

阐明癌症侵袭时 β-KATENIN 与生长因子受体之间的关联和信号转导途径

基本信息

批准号：
09470056
负责人：
OCHIAI Atsushi
金额：
$ 5.38万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

1) Down regulation of the cadherin-mediated cell adhesion and tyrosine phosphoryaltion of β-catenin was stimulated by growth factors as epidermal growth factor (EGF) and transforming growth factor α (TGF α) using human cancer cell lines. Tyrosine phosphrylation of β-catenin was confirmed to be present in human colon cancer tissue at the invasive front where cancer cells dissociate from cancer nests in a single cells.2) Physical association between β-catenin and c-erB-2 was confirmed using deletion mutants of β-catenin. The 12th armadillo repeat which locates at the center of β-catenin was found to bind the growth factor receptors as EGF receptor and c-erB-2. Tyrosine phosphoryaltion of the 12th armadillo repeat was occurred by EGF and TGF α stimulation. These results indicate the presence of signal transduction pathway between growth factor receptor and β-catenin.3) A monoclonal antibody which recognizes tyrosine phosphorylated 12th armadillo repeat of β-catenin was generated using tyrosine phosphoryalted peptides. This antibody allows us to analyze the molecular mechanism of dysfunction of cadherin-mediated cell adhesion system through the growth factor receptor that activation of growth factor receptor phosphoryaltes β-catenin and stimulates dissociation between α and β-catenin.4) Immunohistochemical staining of β-catenin in human colon cancer tissues showed that tyrosine phosphorylation of b-catenin at the 12th armadillo repeat specifically occurs at the invasive front where cancer cells dissociate from cancer nests. These results confirm the presence of signal transduction pathway between growth factor receptor and β-catenin in human cancer tissues and importance of this signal transduction in the cancer invasion and metastasis.

1)表皮生长因子和转化生长因子α等生长因子对人癌细胞株的细胞黏附和β-连环蛋白酪氨酸磷酸化的下调作用。β-连环蛋白的酪氨酸磷酸化被证实存在于侵袭前沿的人结肠癌组织中，癌细胞从单个细胞中的癌巢中解离。2)利用β-连环蛋白的缺失突变体证实了β-连环蛋白和c-erb-2之间的物理联系。位于β-连环蛋白中心的第12重复序列与生长因子受体和c-erb-2结合。在表皮生长因子和转化生长因子α的刺激下，第12重复序列发生酪氨酸磷酸化。这些结果表明生长因子受体和β-连环蛋白之间存在信号转导途径。3)利用酪氨酸磷酸化的多肽制备识别β-连环蛋白酪氨酸磷酸化第12重复序列的单抗。这种抗体使我们能够通过生长因子受体的激活来分析钙粘附素介导的细胞黏附系统功能障碍的分子机制，即生长因子受体激活β-连环蛋白并刺激α和β-连环蛋白之间的解离。4)人结肠癌组织中β-连环蛋白的免疫组织化学染色显示，b-连环蛋白第12重复序列的酪氨酸磷酸化特异地发生在癌细胞从癌巢中解离的侵袭前沿。这些结果证实了肿瘤组织中存在生长因子受体和β-连环蛋白之间的信号转导通路，以及该信号转导通路在肿瘤侵袭和转移中的重要作用。