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A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression

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 proto-oncogene β-catenin for destruction by cytoplasmic proteasomes. In the presence of a...

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Detalles Bibliográficos
Autores principales: Zeineldin, Maged, Cunningham, Jamie, McGuinness, William, Alltizer, Preston, Cowley, Brett, Blanchat, Bryan, Xu, Wenhao, Pinson, David, Neufeld, Kristi L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265630/
https://www.ncbi.nlm.nih.gov/pubmed/21996741
http://dx.doi.org/10.1038/onc.2011.434
Descripción
Sumario: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 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 (Apc(mNLS)). Apc(mNLS/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 Apc(mNLS/mNLS) mice. Compared to Apc(+/+) mice, Apc(mNLS/mNLS) mice displayed increased proliferation in epithelial cells from the jejunum, ileum, and colon. These same tissues from Apc(mNLS/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 Apc(Min/+) mice, which harbor a mutation that truncates Apc, have 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 control of Wnt target genes, intestinal epithelial cell proliferation and polyp formation.