低氧微环境在肿瘤的发生和发展中发挥重要作用。p53作为肿瘤抑制基因如何在低氧刺激下，通过诱导其下游靶基因表达抑制肿瘤细胞增殖，是目前肿瘤微环境研究的热点。申请者前期通过低氧刺激诱导p53活化，筛选并鉴定出一个新的靶基因坍塌调节蛋白3（CRMP3）。根据预实验结果提出科学假说：p53和低氧诱导因子1(HIF1)双重调控CRMP3表达，上调的CRMP3与MAPK信号通路中的MEK1/2结合，进而调节肿瘤细胞增殖和转移。 本课题拟利用我们构建的多种细胞、动物模型，在分子、细胞及整体水平研究p53在低氧微环境中对靶蛋白CRMP3的调控，以及CRMP3抑制肿瘤细胞增殖的分子机制和在肿瘤发生发展中的生物学功能。本研究将阐明p53在低氧微环境中抑制肿瘤的机制，为肿瘤临床诊治提供潜在靶点。

Hypoxia microenvironment plays a crucial role in determine the fate of a tumor and its host. The mechanism of the tumor suppressor wtp53 induces the its target gene to inhibit tumor cell proliferation is currently reserch focus. The applicant has found that the hypoxic stress activated p53 and a new downstream target collapsin response mediator protein-3 (CRMP3). On the basis of these findings, we have formulated the central hypothesis that both p53 and hypoxia inducible factor-1 (HIF1) upregulate CRMP-3 expression, which in turn modulates MAPK signaling to inhibit tumor cell proliferation and metastasis. In this project, we will study the regulation mechanism and antiproliferative function of CRMP3 in the development and progression of cancer. Our research will provide novel insight of explaination of mechanism of a well-known tumor suppressor p53 under hypoxia microenvironment. The objective of this proposal is to analyze contributions of collapsin response mediator protein-3 to the tumor suppressor activity of p53 and provide a practical biomarker of clinical tumor diagnosis.

低氧微环境在肿瘤的发生和发展中发挥重要作用。p53作为肿瘤抑制基因如何在低氧刺激下，通过诱导其下游靶基因表达抑制肿瘤细胞增殖，是目前肿瘤微环境研究的热点。申请者前期通过低氧刺激诱导p53活化，筛选并鉴定出一个新的靶基因坍塌调节蛋白3（CRMP3）。根据预实验结果提出证实：p53和低氧诱导因子1(HIF1)双重调控CRMP3表达，上调的CRMP3与MAPK信号通路中的MEK1/2结合，进而调节肿瘤细胞增殖和转移。本课题利用我们构建的多种细胞、动物模型，在分子、细胞及整体水平研究p53在低氧微环境中对靶蛋白CRMP3的调控，以及CRMP3抑制肿瘤细胞增殖的分子机制和在肿瘤发生发展中的生物学功能。本研究阐明了p53在低氧微环境中抑制肿瘤的机制，为肿瘤临床诊治提供潜在靶点。