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Intestinal Dysplasia and Adenoma in Transgenic Mice after Overexpression of an Activated ß-Catenin¹

Institut National de la Santé et de la Recherche Médicale U129, ICGM, 75014 [B. R., S. S-K., A. P., A-l. P., A. K., C. P.]; Service d’Anatomopathologie, Hôpital Robert Debré, 75019 [D. B., M. P.]; Institut National de la Santé et de la Recherche Médicale U246, Faculté de Médecine Xavier Bichat, Institut Fédératif de Recherche 02, 75810 [A. V.], Paris, France

Mutations in the adenomatous polyposis coli gene or activating mutations in the ß-catenin gene itself are thought to be responsible for the excessive ß-catenin signaling involved in intestinal carcinogenesis. We generated transgenic mice that expressed large amounts of a NH₂-terminally truncated mutant ß-catenin (N131ß-catenin) in the intestine. These mice had multifocal dysplastic lesions in the small intestine, reminiscent of the early lesions observed in the mouse models of familial adenomatous polyposis. The number of apoptotic cells in the villi of these transgenic mice was 3–4-fold higher than in nontransgenic mice. Expression of the truncated ß-catenin mutant in the kidney led to the development of severe polycystic kidney disease.

Our findings support the concept that deregulation of the ß-catenin signaling pathway is the major oncogenic consequence of adenomatous polyposis coli mutations in intestinal neoplasia.

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