The Lautenberg Center for Immunology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Nature. 2011 Feb 17;470(7334):409-13. doi: 10.1038/nature09673.
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.
成熟的肠道在成年期持续快速更新，通常在损伤诱导的微环境中。肠道上皮细胞自我更新的主要驱动力是 Wnt 介导的信号通路，而 Wnt 信号在结直肠癌中经常被过度激活。在这里，我们表明，酪蛋白激酶 Iα（CKIα）是β-连环蛋白降解复合物的一个组成部分，是 Wnt 信号通路的关键调节因子。在肠道中诱导 Csnk1a1（编码 CKIα 的基因）的消融会触发大量的 Wnt 激活，令人惊讶的是，这不会导致肿瘤发生。CKIα 缺陷的上皮细胞除了 Wnt 激活外，还表现出许多人类结直肠肿瘤的特征，特别是诱导 DNA 损伤反应和细胞衰老，这两者都被认为是防止恶性转化的障碍。小鼠的上皮细胞 DNA 损伤反应伴随着 p53 的大量激活，这表明 p53 途径可能抵消 Wnt 过度激活的促肿瘤作用。值得注意的是，人类从良性腺瘤到侵袭性结直肠癌的转变通常与 p53 失活有关，突出了 p53 作为防止恶性进展的安全保障的重要性；然而，p53 介导的肿瘤抑制的机制尚不清楚。我们表明，CKIα 缺陷肠道中肠道内稳态的维持需要 p53 介导的生长控制，因为 Csnk1a1 与 p53 或其靶基因 p21（也称为 Waf1、Cip1、Sdi1 和 Cdkn1a）的联合消融会引发伴有广泛增殖的高级别发育不良。出乎意料的是，这些消融还会迅速诱导非增殖细胞侵入绒毛固有层，导致整个小肠的侵袭性癌。此外，在 p53 缺陷的肠道中，编码 CKIα 的基因的杂合性缺失导致高度侵袭性的癌，表明当 p53 失活时，CKIα 作为一种肿瘤抑制因子发挥作用。我们确定了一组基因（p53 抑制侵袭签名，PSIS），当同时缺失 p53 和 CKIα 时，该基因被激活，这可能解释了侵袭性的快速诱导。PSIS 转录和肿瘤侵袭被 p21 抑制，独立于细胞周期控制。因此，通过抑制 PSIS 表达来抑制组织侵袭是野生型 p53 的一种新的肿瘤抑制功能。
