title: A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression.
abstract: Mutation 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 the 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 cofactor for genes required for cell proliferation such as cyclin-D1 and c-Myc. In cultured cells, APC shuttles between the nucleus and the cytoplasm, with nuclear APC implicated in the inhibition of Wnt target gene expression. Adopting 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 (NLSs) of Apc (Apc(mNLS)). Apc(mNLS/mNLS) mice are viable and fractionation of mouse embryonic fibroblasts (MEFs) isolated from these mice revealed a significant reduction in nuclear Apc as compared with Apc(+/+) MEFs. The levels of Apc and β-catenin protein were not significantly altered in small intestinal epithelia from Apc(mNLS/mNLS) mice. Compared with Apc(+/+) mice, Apc(mNLS/mNLS) mice showed increased proliferation in epithelial cells from the jejunum, ileum and colon. These same tissues from Apc(mNLS/mNLS) mice showed more mRNA from three genes upregulated in response to canonical Wnt signal, c-Myc, axin-2 and cyclin-D1, and less mRNA from Hath-1, which is downregulated in response to Wnt. These observations suggest a role for nuclear Apc in the inhibition of canonical Wnt signaling and the control of epithelial proliferation in intestinal tissue. Furthermore, we found Apc(Min/+) mice, which harbor a mutation that truncates Apc, to have an increased polyp size and multiplicity if they also carry the Apc(mNLS) allele. Taken together, this analysis of the novel Apc(mNLS) mouse model supports a role for nuclear Apc in the control of Wnt target genes, intestinal epithelial cell proliferation and polyp formation.
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors: M
authors: M
authors: Zeineldin
authors: J
authors: J
authors: Cunningham
authors: W
authors: W
authors: McGuinness
authors: P
authors: P
authors: Alltizer
authors: B
authors: B
authors: Cowley
authors: B
authors: B
authors: Blanchat
authors: W
authors: W
authors: Xu
authors: D
authors: D
authors: Pinson
authors: K L
authors: KL
authors: Neufeld
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D019913:Nuclear Localization Signals; D051176:beta Catenin