Abstract
The mature gut renews continuously and rapidly throughout adult life, often in a damage-inflicting micro-environment. The major driving force for self-renewal of the intestinal epithelium is the Wnt-mediated signalling pathway, and Wnt signalling is frequently hyperactivated in colorectal cancer1. Here we show that casein kinase Iα (CKIα), a component of the β-catenin-destruction complex1, is a critical regulator of the Wnt signalling pathway. Inducing the ablation of Csnk1a1 (the gene encoding CKIα) in the gut triggers massive Wnt activation, surprisingly without causing tumorigenesis. CKIα-deficient epithelium shows many of the features of human colorectal tumours in addition to Wnt activation, in particular the induction of the DNA damage response and cellular senescence, both of which are thought to provide a barrier against malignant transformation2. The epithelial DNA damage response in mice is accompanied by substantial activation of p53, suggesting that the p53 pathway may counteract the pro-tumorigenic effects of Wnt hyperactivation. Notably, the transition from benign adenomas to invasive colorectal cancer in humans is typically linked to p53 inactivation, underscoring the importance of p53 as a safeguard against malignant progression3; however, the mechanism of p53-mediated tumour suppression is unknown. We show that the maintenance of intestinal homeostasis in CKIα-deficient gut requires p53-mediated growth control, because the combined ablation of Csnk1a1 and either p53 or its target gene p21 (also known as Waf1, Cip1, Sdi1 and Cdkn1a) triggered high-grade dysplasia with extensive proliferation. Unexpectedly, these ablations also induced non-proliferating cells to invade the villous lamina propria rapidly, producing invasive carcinomas throughout the small bowel. Furthermore, in p53-deficient gut, loss of heterozygosity of the gene encoding CKIα caused a highly invasive carcinoma, indicating that CKIα functions as a tumour suppressor when p53 is inactivated. We identified a set of genes (the p53-suppressed invasiveness signature, PSIS) that is activated by the loss of both p53 and CKIα and which probably accounts for the brisk induction of invasiveness. PSIS transcription and tumour invasion were suppressed by p21, independently of cell cycle control. Restraining tissue invasion through suppressing PSIS expression is thus a novel tumour-suppressor function of wild-type p53.
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Acknowledgements
We thank S. Robine for the Vil1–Cre–ERT2 mice, O. Sansom and B. Romagnolo for intestinal sections of ApcΔgut mice, K. Rajewsky for the pGEM–loxP–Neo–loxP and pCA–NLS–Cre vectors; and E. Horwitz, M. Farago, D. Naor, N. Asherie and D. Knigin for providing expertise and reagents. We are grateful to A. Yaron for critical reading of the manuscript. This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation, the RUBICON EC Network of Excellence, the Israel Cancer Research Fund and Deutsches Krebsforschungszentrum–Ministry of Science and Technology (DKFZ–MOST). Z.W. is supported by a Marie-Curie Intra-European Fellowship.
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Most experiments were performed by E.E., A.P. and R.E.G. Additional experimental work was carried out by Y.M., G.B., G.C., I.S.-A., I.B., R.H.-K. and Z.W. Experimental design and interpretation of data were conducted by all authors. S.J. supervised the gene targeting. The project was supervised by E.P. and Y.B.-N., and the paper was written by E.E., A.P., R.E.G., K.A., M.O., E.P. and Y.B.-N.
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The file contains Supplementary Figures 1-11 with legends, Supplementary Tables 1-3 and references for Supplementary Table 3. (PDF 6938 kb)
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Elyada, E., Pribluda, A., Goldstein, R. et al. CKIα ablation highlights a critical role for p53 in invasiveness control. Nature 470, 409–413 (2011). https://doi.org/10.1038/nature09673
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DOI: https://doi.org/10.1038/nature09673
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