Although Apc is well characterized as a tumor-suppressor gene in the intestine, the precise mechanism of this suppression remains to be defined. Using a novel inducible Ahcre transgenic line in conjunction with a loxPflanked Apc allele we, show that loss of Apc acutely activates Wnt signaling through the nuclear accumulation of ␤-catenin. Coincidentally, it perturbs differentiation, migration, proliferation, and apoptosis, such that Apc-deficient cells maintain a "crypt progenitor-like" phenotype. Critically, for the first time we confirm a series of Wnt target molecules in an in vivo setting and also identify a series of new candidate targets within the same setting.Supplemental material is available at http://www.genesdev.org.

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Based on recent reports that peroxisome proliferatoractivated receptor delta (PPARd) activation promotes tumourigenesis, we have investigated the role of this protein in Apc-mediated intestinal tumourigenesis. We demonstrate that the inactivation of Apc in the adult small intestine, while causing the expected nuclear accumulation of b-catenin, does not cause the expected increase in PPARd mRNA or protein but conversely, the levels of PPARd mRNA and protein are lowered. Furthermore, we find that Apc Min PPARd-null mice exhibit an increased predisposition to intestinal tumourigenesis. Our data suggest that PPARd is not directly regulated by bcatenin, and that inhibition of PPARd activity is unlikely to be an appropriate strategy for the chemoprevention or chemotherapy of intestinal malignancies.

Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer where its loss leads to constitutive activation of β-catenin/TCF4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and others previous studies have shown that although Cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting proliferation following acute Apc loss may be dependent on another D-type Cyclin. In this study we investigated the expression and functional relevance of Cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in CDK4 and hyper-phosphorylated Rb levels. Deficiency of Cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc deficient intestinal epithelium. Moreover Cyclin D2 dramatically reduced tumor growth and development in ApcMin/+ mice. Importantly Cyclin D2 knockout did not affect proliferation of normal enterocytes and furthermore CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from ApcMin/+ mice. Taken together, these results indicate that Cyclin D-CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling and inhibiting this complex may be an effective chemopreventative strategy in colorectal cancer.