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.

The -Catenin Destruction Complex

“…The cytoplasmic isoforms a, d, and 1 can bind to Axin, and purified CK1a, d, or 1 can phosphorylate b-catenin at S45 (Amit et al 2002). RNAi experiments in both mammalian cells and Drosophila and genetic experiments in mice indicate that CK1a is the principal isoform responsible for phosphorylating Ser45 (Liu et al 2002;Matsubayashi et al 2004;Elyada et al 2011).…”

Molecular dynamics of the full-length p53 monomer

“…37 This results in significant changes in its functional properties as a transcription factor. [38][39][40][41][42][43] As a consequence of the p53 isoforms function as a transcription factor and its involvement in DNA damage, it is evident that the status of p53 plays a crucial role in cancer progression [44][45][46][47][48][49][50][51][52] as well in different physiological 2 and anticancer responses. 42 In fact, p53 is frequently mutated in cancer, resulting in novel "gain-of-function"effects.…”

A Screen for X-Linked Mutations Affecting Drosophila Photoreceptor Differentiation Identifies Casein Kinase 1α as an Essential Negative Regulator of Wingless Signaling

“…Consistently, an RNAi screen in Drosophila cultured cells identified CK1a, but not CK1e, as a negative regulator of Wg reporter activity (Dasgupta et al 2005). The conditional ablation of mouse CK1a from intestinal epithelia similarly induces b-Catenin accumulation accompanied by robust activation of many Wnt target genes (Elyada et al 2011). The role of CK1a as the primary family member that negatively regulates Arm/b-catenin thus seems to be conserved across species.…”