title: CKIα ablation highlights a critical role for p53 in invasiveness control.
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 cancer. Here we show that casein kinase Iα (CKIα), a component of the β-catenin-destruction complex, 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 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 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.
authors.affiliation: The Lautenberg Center for Immunology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Elyada
authors.forename: Ariel
authors.initials: A
authors.lastname: Pribluda
authors.forename: Robert E
authors.initials: RE
authors.lastname: Goldstein
authors.forename: Yael
authors.initials: Y
authors.lastname: Morgenstern
authors.forename: Guy
authors.initials: G
authors.lastname: Brachya
authors.forename: Gady
authors.initials: G
authors.lastname: Cojocaru
authors.forename: Irit
authors.initials: I
authors.lastname: Snir-Alkalay
authors.forename: Ido
authors.initials: I
authors.lastname: Burstain
authors.forename: Rebecca
authors.initials: R
authors.lastname: Haffner-Krausz
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Wiener
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D048128:Casein Kinase Ialpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000098551:Prospero-Related Homeobox 1 Protein; D048128:Casein Kinase Ialpha