Details

Autor(en) / Beteiligte

• 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

Titel

CKIα ablation highlights a critical role for p53 in invasiveness control

Ist Teil von

• Nature (London), 2011-02, Vol.470 (7334), p.409-413

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• The role of p53 in metastasis In a mouse model of intestinal cancer, Yinon Ben-Neriah and colleagues show that in the absence of CK1-α, the loss of p53 dramatically enhances tumour progression and metastasis. The tumour repressor p53 normally limits cancer cell invasion through the regulation of p21 and a set of invasion genes that include Prox1. This study adds more detail to the emerging picture that during tumour development, the p53 gene not only controls cell death and proliferation but also metastasis. This study shows, via a mouse model of intestinal cancer, that in the absence of CKIα, the loss of p53 dramatically enhances tumour progression and metastasis. p53 is shown to normally limit cancer cell invasion via the regulation of p21 and a set of invasion genes that include Prox1 . This study adds important insights to the emerging picture that during tumour development the p53 tumour suppressor gene not only controls cell death and proliferation but also metastasis. 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 1 . Here we show that casein kinase Iα (CKIα), a component of the β-catenin-destruction complex 1 , 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 2 . 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 3 ; 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.