Nature、PNAS聚焦明星抑癌基因：p53

　　

生物通报道：从1979年发现至今，P53已经历经30多年的岁月，30年说长不长说短不短，人们对p53基因的认识经历了癌蛋白抗原—癌基因—抑癌基因的三重转变，关于p53的文章层出不穷，每当我们觉得离p53的真相接近之时才发现，p53仍是我们最熟悉的陌生人。最近的Nature，PNAS分别发表了p53最新研究进展，再度拉近了我们与p53真相间的距离。

来自以色列希伯来大学，芬兰赫尔辛基大学等处的研究人员发现了p53这个作用广泛的因子的新功能——促进癌细胞转移。这一研究成果公布在Nature杂志上。

研究人员首先构建了一个小肠癌的小鼠模型，然后进行了基因干扰实验，发现当CKIα 缺失的时候，小鼠中如果丢失了p53会大大增强肿瘤发展和转移，而在正常状态下，这种抑癌因子能通过调控p21，以及包括Prox1在内的一组入侵基因来限制癌细胞入侵。这项研究表明了p53的又一功能：不仅控制细胞死亡和增殖，而且还调控癌细胞转移。

另外一篇文章中，研究人员也发现了p53的一项新功能——抑制癌细胞向更富于侵袭性的干细胞样状态转化。

癌细胞需要获得干细胞的某些特征例如永生性才能生存和适应不断变化的环境。永生能力使得细胞能够不断自我更新，并能生成可分化为其他细胞类型的祖细胞，所有的肿瘤都是由癌细胞组成的不同的细胞聚集物，然而目前我们尚无法了解肿瘤异质性形成的机制。

在这篇文章中，研究人员对乳腺癌和肺癌中的几百个基因表达图谱进行了严密地筛查，寻找干细胞样的标记，检测它们与p53状态的联系。结果发现p53突变或失活的肿瘤与干细胞在基因表达模式上有着密切的联系：p53丧失使得细胞克服了死亡和增殖障碍从而产生了致瘤性。

除此之外，近期中国科学家也获得了p53的相关研究成果，比如朱卫国教授研究组发现一个甲基化缺陷的SIRT1突变体维持了对p53活性的抑制功能。研究结果表明除甲基化作用依赖的机制，Set7/9还可通过SIRT1间接调控p53的功能。这为为阐明p53的活性调控模式及抑制肿瘤细胞生长的机制做出了积极贡献，对探索肿瘤防治新途径具有重要的学术意义和潜在的应用价值。

另外中科大等处的研究人员揭示了p53在调控磷酸戊糖途径(pentose phosphate pathway, PPP)中的作用机制。证明了p53可以与磷酸戊糖途径上的第一步反应的关键酶葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase， G6PD)相结合，并且抑制它的活性。

这些研究对于深入剖析p53这一著名的抑癌基因具有重要的意义。

（生物通：万纹）

原文摘要：

CKIα ablation highlights a critical role for p53 in invasiveness control

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 cancer1. Here we show that casein kinase Iα (CKIα), a component of the β-catenin-destruction complex1, 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 transformation2. 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 progression3; 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.