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dc.contributor.authorZeineldin, Maged
dc.contributor.authorCunningham, Jamie Renee Zerbe
dc.contributor.authorMcGuinness, William
dc.contributor.authorAlltizer, Preston
dc.contributor.authorCowley, Brett
dc.contributor.authorBlanchat, Bryan
dc.contributor.authorXu, Wenhao
dc.contributor.authorPinson, David
dc.contributor.authorNeufeld, Kristi L.
dc.date.accessioned2017-05-11T20:08:36Z
dc.date.available2017-05-11T20:08:36Z
dc.date.issued2011-09-26
dc.identifier.citationZeineldin, Maged et al. “A Knock-in Mouse Model Reveals Roles for Nuclear Apc in Cell Proliferation, Wnt Signal Inhibition and Tumor Suppression.” Oncogene 31.19 (2012): 2423–2437.en_US
dc.identifier.urihttp://hdl.handle.net/1808/24108
dc.description.abstractMutation of the tumor suppressor adenomatous polyposis coli (APC) is considered an initiating step in the genesis of the vast majority of colorectal cancers. APC inhibits the Wnt signaling pathway by targeting proto-oncogene β-catenin for destruction by cytoplasmic proteasomes. In the presence of a Wnt signal, or in the absence of functional APC, β-catenin can serve as a transcription co-factor for genes required for cell proliferation such as cyclin D1 and c-Myc. In cultured cells, APC shuttles between the nucleus and cytoplasm, with nuclear APC implicated in inhibition of Wnt target gene expression. Taking a genetic approach to evaluate the functions of nuclear APC in the context of a whole organism, we generated a mouse model with mutations that inactivate the nuclear localization signals of Apc (ApcmNLS). ApcmNLS/mNLS mice are viable and fractionation of embryonic fibroblasts (MEFs) isolated from these mice revealed a significant reduction in nuclear Apc compared to Apc+/+ MEFs. The levels of Apc and β-catenin protein were not significantly altered in small intestinal epithelia from ApcmNLS/mNLS mice. Compared to Apc+/+ mice, ApcmNLS/mNLS mice displayed increased proliferation in epithelial cells from the jejunum, ileum, and colon. These same tissues from ApcmNLS/mNLS mice displayed more mRNA from three genes up-regulated in response to canonical Wnt signal, c-Myc, Axin2, and Cyclin D1, and less mRNA from Hath 1 which is down-regulated in response to Wnt. These observations suggest a role for nuclear Apc in inhibition of canonical Wnt signaling and control of epithelial proliferation in intestinal tissue. Furthermore, we found ApcMin/+ mice, which harbor a mutation that truncates Apc, have increased polyp size and multiplicity if they also carry the ApcmNLS allele. Taken together, this analysis of the novel ApcmNLS mouse model supports a role for nuclear Apc in control of Wnt target genes, intestinal epithelial cell proliferation and polyp formation.en_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttps://www.nature.com/onc/journal/v31/n19/full/onc2011434a.htmlen_US
dc.rightsCopyright Nature Publishing Groupen_US
dc.titleA knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppressionen_US
dc.typeArticleen_US
kusw.kuauthorNeufeld, Kristi L.
kusw.kudepartmentMolecular Biosciencesen_US
dc.identifier.doi10.1038/onc.2011.434en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3265630en_US
dc.rights.accessrightsopenAccess


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