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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  1. 1.

    Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006)

  2. 2.

    et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006)

  3. 3.

    & A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990)

  4. 4.

    et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 18, 1385–1390 (2004)

  5. 5.

    et al. Senescence in premalignant tumours. Nature 436, 642 (2005)

  6. 6.

    et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006)

  7. 7.

    & p53—a Jack of all trades but master of none. Nature Rev. Cancer 9, 821–829 (2009)

  8. 8.

    et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997)

  9. 9.

    , , , & Deregulated β-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBO J. 20, 4912–4922 (2001)

  10. 10.

    Divorcing ARF and p53: an unsettled case. Nature Rev. Cancer 6, 663–673 (2006)

  11. 11.

    , , & Mdm4 loss in the intestinal epithelium leads to compartmentalized cell death but no tissue abnormalities. Differentiation 77, 442–449 (2009)

  12. 12.

    , , & Radiation-induced p53 and p21WAF-1/CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest. Am. J. Pathol. 153, 899–909 (1998)

  13. 13.

    , , & Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008)

  14. 14.

    et al. Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132, 1443–1451 (2005)

  15. 15.

    et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl Acad. Sci. USA 91, 8969–8973 (1994)

  16. 16.

    & Mouse models of colon cancer. Gastroenterology 136, 780–798 (2009)

  17. 17.

    Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992)

  18. 18.

    et al. Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas. Proc. Natl Acad. Sci. USA 94, 10199–10204 (1997)

  19. 19.

    et al. A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer 8, 162 (2008)

  20. 20.

    et al. Identification of the IFITM family as a new molecular marker in human colorectal tumors. Cancer Res. 66, 1949–1955 (2006)

  21. 21.

    et al. IFN-induced transmembrane protein 1 promotes invasion at early stage of head and neck cancer progression. Clin. Cancer Res. 14, 6097–6105 (2008)

  22. 22.

    et al. Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13, 407–419 (2008)

  23. 23.

    , , , & Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev. 22, 746–755 (2008)

  24. 24.

    et al. p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104, 1633–1639 (1993)

  25. 25.

    et al. The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation. Mol. Syst. Biol. 1, 2005.0022 (2005)

  26. 26.

    & p21 in cancer: intricate networks and multiple activities. Nature Rev. Cancer 9, 400–414 (2009)

  27. 27.

    et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nature Cell Biol. 11, 694–704 (2009)

  28. 28.

    et al. Mutant p53 drives invasion by promoting integrin recycling. Cell 139, 1327–1341 (2009)

  29. 29.

    et al. Adenoma–carcinoma sequence or ‘de novo’ carcinogenesis? A study of adenomatous remnants in a population-based series of large bowel cancers. Cancer 69, 883–888 (1992)

  30. 30.

    , , & The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010)

  31. 31.

    , , & Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase. Transgenic Res. 7, 105–112 (1998)

  32. 32.

    et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004)

  33. 33.

    et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genet. 29, 418–425 (2001)

  34. 34.

    et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995)

  35. 35.

    et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004)

  36. 36.

    et al. A selective decrease in the β cell mass of human islets transplanted into diabetic nude mice. Transplantation 59, 817–820 (1995)

  37. 37.

    & Molecular and cell biology of replicative senescence. Cold Spring Harb. Symp. Quant. Biol. 59, 67–73 (1994)

  38. 38.

    , , , & Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc. Natl Acad. Sci. USA 93, 11382–11388 (1996)

  39. 39.

    et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996)

  40. 40.

    , , & Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells. Mol. Cancer Ther. 4, 281–290 (2005)

  41. 41.

    et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003)

  42. 42.

    & DiRE: identifying distant regulatory elements of co-expressed genes. Nucleic Acids Res. 36, W133–W139 (2008)

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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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Author notes

    • Ela Elyada
    •  & Ariel Pribluda

    These authors contributed equally to this work.


  1. The Lautenberg Center for Immunology, IMRIC, Hebrew University—Hadassah Medical School, Jerusalem 91120, Israel

    • Ela Elyada
    • , Ariel Pribluda
    • , Robert E. Goldstein
    • , Yael Morgenstern
    • , Guy Brachya
    • , Gady Cojocaru
    • , Irit Snir-Alkalay
    • , Ido Burstain
    • , Eli Pikarsky
    •  & Yinon Ben-Neriah
  2. Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel

    • Rebecca Haffner-Krausz
  3. Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel

    • Steffen Jung
  4. Molecular Cancer Biology Program and the Institute for Molecular Medicine Finland, Biomedicum Helsinki, University of Helsinki, Helsinki 00014, Finland

    • Zoltan Wiener
    •  & Kari Alitalo
  5. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel

    • Moshe Oren
  6. Department of Pathology, IMRIC, Hebrew University—Hadassah Medical School, Jerusalem 91120, Israel

    • Eli Pikarsky


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eli Pikarsky or Yinon Ben-Neriah.

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