Abstract 1978: Demonstrating a role for nuclear Adenomatous polyposis coli in intestinal cell differentiation.

Abstract

Abstract Colon cancer is the second leading cause of cancer-related mortality in the United States, resulting in over 50,000 deaths annually. Approximately 80% of colon cancers begin with a mutation in the gene coding for the tumor suppressor protein Adenomatous Polyposis Coli, APC. APC protein can shuttle between the cytoplasm and the nucleus of cells, facilitated by two nuclear localization signals (NLS) and multiple nuclear export signals. To better understand functions of nuclear APC, our lab generated a “knock-in” mouse model with mutations introduced that inactivate both Apc NLS. These ApcmNLS/mNLS mice show a dramatic decrease in nuclear Apc. We previously showed increased proliferation and Wnt target gene expression in intestinal epithelial cells from ApcmNLS/mNLS mice, suggesting a role for nuclear APC in inhibition of proliferation and Wnt signaling. We also showed increased tumor number and size in ApcMin mice if they also harbor the ApcmNLS allele. Here we examine the role of nuclear Apc in intestinal epithelial differentiation and stem cell homeostasis. Paraffin-embedded tissue from the intestines of Apc+/+ and ApcmNLS/mNLS mice was sectioned and stained for markers of enterocytes (alkaline phosphatase) and goblet cells (alcian blue). Quantification of the positive cells indicated that ApcmNLS/mNLS mice had fewer differentiated enterocytes and goblet cells than their wild-type littermates. Intestines from ApcmNLS/mNLS mice were also stained for markers of quiescent and active stem cells, DCAMKL-1 and Lgr5 respectively. Quantification of the various stem cell populations will be described. Together, our data supports a role for nuclear Apc in promoting enterocyte and goblet cell differentiation, in suppression of tumors, and in inhibiting intestinal cell proliferation and Wnt signaling. Information gathered from analysis of ApcmNLS/mNLS mice will contribute to our understanding of the functions of nuclear APC in tumor suppression and ultimately the mechanism of intestinal tumorigenesis. Citation Format: Matthew A. Miller, Maged Zeineldin, Kristi L. Neufeld. Demonstrating a role for nuclear Adenomatous polyposis coli in intestinal cell differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1978. doi:10.1158/1538-7445.AM2013-1978