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Stabilized ß-Catenin Immortalizes Colonic Epithelial Cells¹

Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

The majority of colonic neoplasias contain mutations in either the adenomatous polyposis coli or the ß-catenin (ß-cat) gene, both of which result in elevated levels of cytoplasmic ß-cat. The oncogenic activity of ß-cat has been explored in vivo and in vitro with conflicting results. We tested the hypothesis that ß-cat is capable of immortalizing and transforming cultured epithelial cells that represent the precursors to colon cancer. A truncated form of ß-cat (N89) was stably expressed in murine colonic epithelial cells that were conditionally immortalized by temperature-sensitive T antigen expression and contained a mutant Apc^Min allele [Immorto-Min colonic epithelium (IMCE)]. IMCE cells, grown under nonpermissive conditions, were immortalized by expression of the truncated ß-cat protein as determined by sustained growth in culture and escape from senescence as measured by endogenous ß-galactosidase activity. IMCE neo cells at nonpermissive conditions underwent extensive apoptosis, an effect that was blocked by the expression of N89ß-catenin. IMCE ß-cat cells had significantly lower p19 and p53 protein levels compared to IMCE neo cells, suggesting that alterations in these two key genes may mediate the effects of ß-cat on both cellular senescence and apoptosis. IMCE ß-cat cells were also transformed as determined by growth in the absence of serum, anchorage-independent growth, and sustained tumor growth in nude mice. Stable ß-cat-expressing populations could not be generated in conditionally immortalized colonic epithelial cells with a wild-type Apc background. These studies demonstrated the immortalizing activity of stabilized ß-cat for the first time and extend the transforming ability of mutated ß-cat to a cell line representing a precursor to colorectal cancer.

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