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Proteomic Analysis of Intestinal Epithelial Cells Expressing Stabilized ß-Catenin¹

Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045 [Ma. S., T. K., Y. M., T. Y., S. H.]; Fourth Department of Internal Medicine, Nippon Medical School, Tokyo 113-8603 [Ma. S., A. G., S. K.]; and Department of Pathology, Keio University School of Medicine, Tokyo 160-8582 [Mi. S.], Japan

Aberrant accumulation of ß-catenin protein because of mutation of either the ß-catenin or adenomatous polyposis coli gene plays an essential role in the development of colorectal carcinoma. We established previously a stable clone of the rat small intestinal epithelial cell line IEC6, which is capable of inducing stabilized ß-catenin protein lacking NH₂-terminal glycogen synthase kinase-3ß phosphorylation site under a strict control of the tetracycline-regulatory system. This clone, IEC6-TetOFF-ß-catenin N89, shows in vitro polypoid growth on the removal of doxycycline and seems to be an appropriate model for analyzing the molecular mechanisms of early intestinal carcinogenesis. Of >2000 protein spots displayed by newly developed two-dimensional difference gel electrophoresis, 22 were found to be up- or down-regulated on the induction of stabilized ß-catenin. The majority of these proteins fell into two categories: (a) redox-status regulatory proteins and (b) cytoskeleton-associated proteins. Representatively, a key redox-status regulatory protein, manganese superoxide dismutase, up-regulated in IEC6 cells expressing stabilized ß-catenin protein, was overexpressed in adenoma and adenocarcinoma cells of familial adenomatous polyposis patients in parallel with the accumulation of ß-catenin. These results suggest that aberrant accumulation of ß-catenin might contribute to colorectal carcinogenesis by affecting redox status in the mitochondria of intestinal epithelial cells.

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