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The Threshold Level of Adenomatous Polyposis Coli Protein for Mouse Intestinal Tumorigenesis

¹ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and ² Department of Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Makoto M. Taketo, Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-konoé-cho, Sakyo-ku, Kyoto, Japan. Phone: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp.

The adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/ß-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 Apc⁷¹⁶ mice, heterozygotes of an Apc null allele. Like in Apc⁷¹⁶ 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 ß-catenin accumulation and ß-catenin/T-cell factor transcriptional activity. These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the ß-catenin/T-cell factor transcription. We further estimated the threshold of APC protein level that forms one polyp per mouse as 15% of the wild type. These results also suggest therapeutic implications concerning Wnt signaling inhibitors.

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