Publication Date:
2011-02-19
Description:
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 cancer. Here we show that casein kinase Ialpha (CKIalpha), a component of the beta-catenin-destruction complex, is a critical regulator of the Wnt signalling pathway. Inducing the ablation of Csnk1a1 (the gene encoding CKIalpha) in the gut triggers massive Wnt activation, surprisingly without causing tumorigenesis. CKIalpha-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 transformation. 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 progression; however, the mechanism of p53-mediated tumour suppression is unknown. We show that the maintenance of intestinal homeostasis in CKIalpha-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 CKIalpha caused a highly invasive carcinoma, indicating that CKIalpha 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 CKIalpha 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elyada, Ela -- Pribluda, Ariel -- Goldstein, Robert E -- Morgenstern, Yael -- Brachya, Guy -- Cojocaru, Gady -- Snir-Alkalay, Irit -- Burstain, Ido -- Haffner-Krausz, Rebecca -- Jung, Steffen -- Wiener, Zoltan -- Alitalo, Kari -- Oren, Moshe -- Pikarsky, Eli -- Ben-Neriah, Yinon -- England -- Nature. 2011 Feb 17;470(7334):409-13. doi: 10.1038/nature09673.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Lautenberg Center for Immunology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331045" target="_blank"〉PubMed〈/a〉
Keywords:
Adenoma/enzymology/genetics/metabolism/pathology
;
Animals
;
Casein Kinase Ialpha/*deficiency/genetics/metabolism
;
Cell Aging
;
Cell Line
;
Cell Line, Tumor
;
Cell Proliferation
;
Cell Transformation, Neoplastic
;
Colorectal Neoplasms/enzymology/genetics/metabolism/*pathology
;
Cyclin-Dependent Kinase Inhibitor p21/deficiency/genetics/metabolism
;
DNA Damage
;
Disease Progression
;
Female
;
Fibroblasts
;
Genes, APC
;
Genes, Tumor Suppressor
;
Homeodomain Proteins/genetics/metabolism
;
Humans
;
Intestinal Mucosa/enzymology/metabolism/pathology
;
Loss of Heterozygosity
;
Male
;
Mice
;
Mice, Knockout
;
Neoplasm Invasiveness/pathology
;
Signal Transduction
;
Tumor Suppressor Protein p53/deficiency/genetics/*metabolism
;
Tumor Suppressor Proteins/deficiency/genetics/metabolism
;
Wnt Proteins/metabolism
;
beta Catenin/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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