| Autor: |
Yan, Zhongfa, Deng, Xiaobing, Chen, Mingxing, Xu, Ying, Ahram, Mamoun, Sloane, Bonnie F., Friedman, Eileen |
| Zdroj: |
Journal of Biological Chemistry; October 1997, Vol. 272 Issue: 44 p27902-27907, 6p |
| Abstrakt: |
Colon carcinomas commonly contain mutations in Ki-ras4B, but very rarely in Ha-ras, suggesting that different Ras isoforms may have distinct functions in colon epithelial cell biology. In an earlier study we had demonstrated that oncogenic Ki-ras4BVal-12, but not oncogenic Ha-rasVal-12, blocks the apicobasal polarization of colon epithelial cells by preventing normal glycosylation of the integrin β1 chain of the collagen receptor. As a result, only the Ki-rasmutated cells exhibited altered cell to substratum attachment, whereas mutation of either Ras isoform activated mitogen-activated protein kinases. We have now asked whether intercellular adhesion proteins implicated in establishing basolateral polarity in colon epithelial cells are modulated by oncogenic Ki-Ras4BVal-12proteins but not oncogenic Ha-RasVal-12proteins. The embryonic adhesion protein carcinoembryonic antigen (CEA) was up-regulated on the mRNA and protein levels in each of three stable Ki-rasVal-12transfectant lines but in none of three stable Ha-rasVal-12transfectant lines. The elevated protein levels of CEA in Ki-ras4BVal-12transfectant cells were decreased by blocking expression of Ki-ras4BVal-12with antisense oligonucleotides. N-cadherin levels were decreased in only the Ki-rastransfectants, whereas E-cadherin levels were unchanged. Immunohistochemical analysis demonstrated that Ki-ras4BVal-12transfectant cells did not polarize into cells with discrete apical and basal regions and so could not restrict expression of CEA to the apical region. These unpolarized cells displayed elevated levels of CEA all along their surface membrane where CEA mediated random, multilayered associations of tumor cells. This aggregation was both calcium-independent and blocked by Fab′ fragments of anti-CEA monoclonal antibody col-1. Trafficking of the lysosomal cysteine protease cathepsin B may also be altered when cell polarity cannot be established. Ki-ras4BVal-12transfectant cells expressed 2-fold elevated protein levels of the lysosomal cysteine protease cathepsin B but did not up-regulate cathepsin B mRNA expression. One function of oncogenic c-Ki-Ras proteins in colon cancer progression may be to up-regulate CEA and thus to prevent the lateral adhesion of adjacent colon epithelial cells that normally form a monolayer in vivo. |
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