Targeted inactivation of CTNNB1 reveals unexpected effects of beta-catenin mutation.
Inactivating mutations of the adenomatous polyposis coli gene (APC) or activating mutations of the beta-catenin gene (CTNNB1) initiate colorectal neoplasia. To address the biochemical and physiologic effects of mutant beta-catenin, we disrupted either the mutant or wild-type CTNNB1 allele in a human colorectal cancer cell line. Cells with only wild-type beta-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 beta-catenin bound less well to E-cadherin than did wild-type beta-catenin, and the membranous localization of wild-type and mutant beta-catenin was accordingly distinct. These findings pose several challenges to current models of APC/beta-catenin function.
Chan
Timothy A
TA
The Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231, USA.
Wang
Zhenghe
Z
Dang
Long H
LH
Vogelstein
Bert
B
Kinzler
Kenneth W
KW
D022202:Chromosomes, Artificial, Bacterial; D015179:Colorectal Neoplasms; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006579:Heterozygote; D006801:Humans; D007438:Introns; D016296:Mutagenesis; D012323:RNA Processing, Post-Transcriptional; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin