Related Experiment Video
Updated: Aug 15, 2026
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis
Qin Li1, Tomo-O Ishikawa, Masanobu Oshima
1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract:
The adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/beta-catenin pathway. To investigate the dose-dependent effects of APC protein in suppressing intestinal tumorigenesis, we constructed mutant mice carrying hypomorphic Apc alleles Apc(neoR) and Apc(neoF) whose expression levels were reduced to 20% and 10% of the wild type, respectively. Although both hypomorphic heterozygotes developed intestinal polyps, tumor multiplicities were much lower than that in Apc(Delta716) mice, heterozygotes of an Apc null allele. Like in Apc(Delta716) mice, loss of the wild-type Apc allele was confirmed for all polyps examined in the Apc(neoR) and Apc(neoF) mice. In the embryonic stem cells homozygous for these hypomorphic Apc alleles, the level of the APC protein was inversely correlated with both the beta-catenin accumulation and beta-catenin/T-cell factor transcriptional activity. These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the beta-catenin/T-cell factor transcription. We further estimated the threshold of APC protein level that forms one polyp per mouse as approximately 15% of the wild type. These results also suggest therapeutic implications concerning Wnt signaling inhibitors.
Insights
Reduced adenomatous polyposis coli (APC) protein levels increase intestinal polyp formation by activating Wnt/beta-catenin signaling. This study quantifies APC
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Adenomatous polyposis coli (APC) gene mutations cause familial adenomatous polyposis.
- APC is a key negative regulator of the Wnt/beta-catenin pathway.
- Wnt/beta-catenin signaling is crucial in intestinal tumorigenesis.
Purpose of the Study:
- To investigate the dose-dependent role of APC protein in suppressing intestinal tumors.
- To determine the quantitative relationship between APC protein levels and polyp formation.
- To explore therapeutic strategies targeting Wnt signaling.
Main Methods:
- Construction of mice with hypomorphic Apc alleles (Apc(neoR), Apc(neoF)) with reduced APC protein expression.
- Analysis of intestinal polyp multiplicity in mutant mice compared to Apc null heterozygotes.
- Examination of APC protein levels, beta-catenin accumulation, and TCF transcriptional activity in embryonic stem cells.
Main Results:
- Hypomorphic Apc heterozygotes developed fewer intestinal polyps than Apc null heterozygotes.
- Loss of the wild-type Apc allele was observed in all examined polyps.
- Reduced APC protein levels correlated with increased beta-catenin accumulation and Wnt/beta-catenin transcriptional activity.
- The threshold for polyp formation was estimated at approximately 15% of wild-type APC protein levels.
Conclusions:
- APC protein levels quantitatively influence intestinal polyp multiplicity.
- Reduced APC protein promotes tumorigenesis via enhanced Wnt/beta-catenin signaling.
- Findings suggest potential therapeutic targets within the Wnt signaling pathway for intestinal polyposis.
