%0 Journal Article
%T Tissue-Specific Effects of Reduced ¦Â-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium
%A Ying Feng&nbsp
%A Naoya Sakamoto&nbsp
%A Rong Wu&nbsp
%A Jie-yu Liu&nbsp
%A Alexandra Wiese&nbsp
%A Maranne E. Green&nbsp
%A Megan Green&nbsp
%A Aytekin Akyol&nbsp
%A Badal C. Roy&nbsp
%A Yali Zhai
%J PLOS Genetics
%D 2015
%I Public Library of Science (PLoS)
%R 10.1371/journal.pgen.1005638
%X Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the ¦Â-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding ¦Â-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in ¦Â-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key ¦Â-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for ¦Â-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for ¦Â-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active ¦Â-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected ¦Â-catenin levels and some ¦Â-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected ¦Â-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.
%U http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1005638