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[Cancer Research 60, 1671-1676, March 15, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

The ß-Catenin Binding Domain of Adenomatous Polyposis Coli Is Sufficient for Tumor Suppression1

Ie-Ming Shih, Jian Yu, Tong-Chuan He, Bert Vogelstein and Kenneth W. Kinzler2

Johns Hopkins Oncology Center, Baltimore, Maryland 21231 (I-M. S., J. Y., T-C. H., B. V., K. W. K.); Department of Pathology, Johns Hopkins Medical Institution, Baltimore, Maryland 21287 (I-M. S.); and Howard Hughes Medical Institutes, Johns Hopkins University, Baltimore, Maryland 20815 (B. V.)

Inactivation of the adenomatous polyposis coli (APC) gene is a critical event in the development of human colorectal cancers. At the biochemical level, several functions have been assigned to the multidomain APC protein, but the cellular effects of APC expression and how they relate to its biochemical functions are less well defined. To address these issues, we generated a recombinant adenovirus (Ad-CBR) that constitutively expresses the central third of APC, which includes all of the known ß-catenin binding repeats. When expressed in colon cancer cells, Ad-CBR blocked the nuclear translocation of ß-catenin and inhibited ß-catenin/Tcf-4-mediated transactivation. Accordingly, expression of endogenous targets of the APC/ß-catenin/Tcf-4 pathway was down-regulated. Ad-CBR infection of colorectal cancer cell lines with mutant APC but wild-type ß-catenin resulted in substantial growth arrest followed by apoptosis. These effects were attenuated in lines with wild-type APC but with mutated ß-catenin. These findings suggest that the ß-catenin-binding domain in the central third of APC is sufficient for its tumor suppressor activity.




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