Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 12, Pages 8265-8270Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.082240999
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- NCI NIH HHS [CA 57345, R01 CA057345, R37 CA043460, CA 43460, R37 CA057345] Funding Source: Medline
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Inactivating mutations of the adenomatous polyposis coli gene (APC) or activating mutations of the P-catenin gene (CTNNB1) initiate colorectal neoplasia. To address the biochemical and physiologic effects of mutant P-catenin, we disrupted either the mutant or wild-type CTNNB1 allele in a human colorectal cancer cell line. Cells with only wild-type P-catenin had decreased colony-forming ability when plated at low density, although their growth was similar to that of parental cells when passaged under routine conditions. Immunohistochemistry and cell-fractionation studies suggested that mutant beta-catenin activity was distinguished primarily by cellular localization and not by protein degradation. Surprisingly, we found mutant P-catenin bound less well to E-cadherin than did wild-type beta-catenin, and the membranous localization of wild-type and mutant P-catenin was accordingly distinct. These findings pose several challenges to current models of APC/beta-catenin function.
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