Reference SummaryZeineldin M, Oncogene 2012 May 10;31(19):2423-37
Title |
A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor suppression. | ||||
Authors |
Zeineldin M; Cunningham J; McGuinness W; Alltizer P; Cowley B; Blanchat B; Xu W; Pinson D; Neufeld KL | ||||
Journal |
Oncogene | ||||
Volume |
31 | ||||
Issue |
19 | ||||
Year |
2012 | ||||
Pages |
2423-37 | ||||
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 beta-catenin for destruction by cytoplasmic proteasomes. In the presence of a Wnt signal, or in the absence of functional APC, beta-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 beta-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. | ||||
Links |
J:186132 – MGI References 21996741 – National Library of Medicine/PubMed |
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Strain Notes
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| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| B6;129-Apctm1.1Klne | Intestine - Large Intestine - Colon lesion | Intestine - Large Intestine - Colon |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
90.91 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
62.5 |
||
| B6;129-Apctm1.1Klne | Intestine - Large Intestine - Colon polyp - dysplastic | Intestine - Large Intestine - Colon |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Duodenum polyp | Intestine - Small Intestine - Duodenum |
45.45 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Intestine - Small Intestine - Duodenum polyp | Intestine - Small Intestine - Duodenum |
62.5 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Ileum polyp | Intestine - Small Intestine - Ileum |
100 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Intestine - Small Intestine - Ileum polyp | Intestine - Small Intestine - Ileum |
100 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Jejunum polyp | Intestine - Small Intestine - Jejunum |
100 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Intestine - Small Intestine - Jejunum polyp | Intestine - Small Intestine - Jejunum |
100 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine polyp | Intestine - Small Intestine |
100 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Intestine - Small Intestine polyp | Intestine - Small Intestine |
100 |
||
| B6;129-Apctm1.1Klne/+ | Intestine - Small Intestine polyp - adenomatous | Intestine - Small Intestine |
0 |
||
| B6.129-Apctm1.1Klne/J | Stomach polyp | Stomach |
observed |
||
| C57BL/6J-ApcMin/+ | Stomach polyp | Stomach |
45.45 |
||
| C57BL/6J-ApcMin/Apctm1.1Klne | Stomach polyp | Stomach |
62.5 |