Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase
Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase
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DOI：
10.1073/pnas.96.9.4874
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发表时间：
1999-04-27
影响因子：
11.1
通讯作者：
Fukui, Y
中科院分区：
文献类型：
--
作者：
Kobayashi, M;Nagata, S;Fukui, Y
印戒细胞癌是胃低分化腺癌的一种恶性类型，其特点是偶见印戒样癌细胞。我们发现，在高分化腺癌细胞系中表达具有结构性活性的磷脂酰肌醇3-激酶(PI-3-Kinase)导致细胞-细胞接触丧失，部分细胞变形为印戒状细胞样，其特征是细胞质中出现粘液滴，内质网和高尔基复合体发达。表达活性的PI3K细胞在裸鼠体内形成低分化肿瘤？这与最初的细胞系明显不同。抗酪氨酸免疫沉淀物中的PI-3-K活性在几种印戒细胞癌细胞系中高于其他腺癌细胞系。此外，在6个印戒细胞中，有4个细胞中的PI-3-K与200 kDa酪氨酸磷酸化的蛋白有关，而在其他细胞系中则没有，提示PI-3-K可能通过与200-kDa蛋白结合而在这些细胞中被激活。200 kDa的蛋白-PI3-激酶复合体仅在膜组分中被分离。用抗磷酸酪氨酸抗体制备的PI3K免疫沉淀物比用抗PI3K抗体制备的PI3K免疫沉淀物的比活力高近3倍。这些结果表明，印戒细胞癌中的PI3K被募集到膜上，并被200 kDa的蛋白结合而激活。
Signet ring cell carcinoma is a malignant type of poorly differentiated adenocarcinomas in stomach, which is characterized by the occasional presence of signet ring like cancer cells. We found that expression of constitutively active phosphatidylinositol 3-kinase (PI 3-kinase) in well differentiated adenocarcinoma cell lines induced the loss of cell-cell contact and some of the cells changed their shapes to signet ring cell-like, characterized by appearance of mucus droplets in the cytoplasm with well developed endplasmic reticulum and Golgi complexes. The active PI 3-kinase-expressing cells formed poorly differentiated tumors in nude mice? which were clearly different from those of the original cell lines. The PI 3-kinase activities detected in antiphosphotyrosine immunoprecipitates were higher in several signet ring cell carcinoma-derived cell lines than in other adenocarcinoma cell lines. In addition, PI 3-kinase was found to be associated with a 200-kDa protein phosphorylated in tyrosine in 4 of 6 signet ring cells but not in other cell lines, suggesting that PI 3-kinase is possibly activated in these cells by binding to the 200-kDa protein. The 200-kDa protein-PI 3-kinase complex was exclusively fractionated in the membrane fractions. The specific activity of the PI 3-kinase immunoprecipitated with anti-phosphotyrosine antibody was approximate to 3-fold higher than that with anti-PI 3-kinase antibody. These results suggest that PI 3-kinase in signet ring cell carcinoma is recruited to the membrane and activated by the binding to the 200-kDa protein.