申请人系统地探讨了重要抑癌蛋白p53相关信号通路的调控机制及其在肿瘤细胞恶性转化中的作用。1）解析了p53调控蛋白ARF表达水平在体内被严格调控的分子基础，并揭示了p53参与调控脂代谢和体细胞重编程的重要作用，加深了人们对p53作用机制的理解；2）阐明了受p53调控的长片断非编码RNA—lincRNA-p21介导了低氧对肿瘤细胞瓦伯格效应的促进作用及机制，为肿瘤细胞瓦伯格效应形成提供新观点；3）解析了癌蛋白XIAP通过调节Mdm2-p53通路抑制细胞自噬，从全新的角度揭示了XIAP促进肿瘤形成的原因；4）揭示了tRNA具有抑制细胞凋亡的新功能，为肿瘤细胞高表达tRNA这一现象提供新解释。共发表Molecular Cell等SCI论文25篇，第一或通讯作者论文20篇。本项目将在已有的工作基础上，深入研究长片断非编码RNA在p53功能调控中的作用，期望全面揭示p53发挥肿瘤抑制功能的分子基础。

The p53 tumor suppressor maintains the normal growth control and genomic stability by either imposing a G1 cell cycle arrest or inducing apoptosis and senescence. Inactivation of p53 pathway has been associated with more than half of all examined human cancers. The main focus of my research has been elucidation of the signaling pathways mediated by p53 and its related molecules, as well as their potential roles in regulating tumor cell malignant transformation. The research achievements are highlighted as the following. 1) Elucidation of the detailed mechanisms whereby the tumor suppressor protein ARF is strictly regulated at post-translational levels. This provides novel insights into the tumor suppressive function of the ARF/p53 axis. 2) Exploration of the molecular mechanisms underlying p53 function in the regulation of lipid metabolism and somatic cell reprogramming. This adds the complexity to the versatile functions of tumor suppressor protein p53, and implicates p53 as a key node that connects different cellular processes. 3) Identification of lincRNA-p21, a p53-responsive long non-coding RNA, as an important player in the regulation of the Warburg effect under hypoxic conditions. 4) Demonstration of a novel and unexpected function of XIAP in negatively modulating autophagic process via regulating the Mdm2-p53 pathway. This partially explains why XIAP functions as an oncogenic molecular to promote tumorigenesis. 5) Demonstration of a crucial role of tRNA in negatively regulating apoptosis. This indicates that high levels of tRNA in cancer cells may promote tumorigenesis through antagonizing apoptosis, and implicates tRNA as a valuable target for anti-cancer therapy. Taken together, these findings generate novel insights into the molecular mechanisms of tumorigenesis mediated by p53-related signaling pathway. In this study, we will further investigate whether p53 exerts its tumor suppressive function through regulating long non-coding RNA. This study will likely provide the base to better understand how p53 inhibits tumor initiation and progression.

p53是迄今为止所发现的人类肿瘤相关性最高的基因之一，其突变发生在人类超过一半的肿瘤中，p53也被认为是人体内防止肿瘤发生最为重要的捍卫者。因此，深入系统地研究p53相关的信号通路及其在肿瘤发生发展中的作用将可能为肿瘤发病机制的解析带来突破，并有可能为肿瘤治疗提供新的潜在靶点。正因为p53具有很强的抑癌功能，其蛋白水平在细胞内需要被严格控制，然而p53蛋白水平在细胞内如何被精确控制的机制还不是很清晰。另外，虽然p53的抑癌功能已被广泛认识，然而其如何发挥抑癌功能并不是很明确。本项目围绕两个科学问题进行集中研究：1）p53蛋白水平在细胞内如何被精确调控？2）长片段非编码RNA是否及如何调控p53的抑癌功能？我们的研究发现MARCH7作为一个E3泛素连接酶结合并催化Mdm2形成K63-依赖的多聚泛素链，从而稳定Mdm2的蛋白水平，最终促进p53的多聚泛素化及蛋白降解；在功能上，MARCH7通过p53控制细胞增殖、细胞凋亡以及肿瘤形成；这一工作揭示了一种全新的Mdm2和p53蛋白稳定性调控模式，并暗示MARCH7能够作为一个潜在的肿瘤干预靶点。另外，我们还发现一个受p53转录上调的长链非编码RNA-TRMP能够通过结合PTBP1调节细胞周期蛋白p27的蛋白翻译，从而调控细胞周期G1-S期运转；在功能上，TRMP能够通过p27精确控制细胞增殖、细胞周期运转以及肿瘤形成；这一工作揭示了抑癌蛋白p53通过长非编码RNA调控细胞周期运转的新机制，并暗示TRMP可能是一个新的肿瘤干预潜在靶点。在本项目的大力资助下，项目负责人以通讯作者的身份在国际知名期刊EMBO Reports和Autophagy上发表SCI学术论文两篇。