TR3相互作用新蛋白机理研究

项目名称： TR3相互作用新蛋白机理研究

项目编号： No.30871281

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 电工技术

项目作者： 吴乔

作者单位： 厦门大学

项目金额： 34万元

中文摘要： TR3是孤儿受体，参与细胞增殖和死亡调节。我们发现：1) 在Apcmin/+小鼠中TR3缺失使肠道肿瘤数量增加。TR3与βatenin结合导致βatenin和TCF4解离；TR3与TCF4结合抑制辅抑制子募集到Wnt下游基因启动子 (Gut, 2011)。 2) TR3抑制Ku80结合到DNA末端，进而抑制DNA双链断裂修复。同时，DNA-PK磷酸化的TR3加强p53转录活性，从而加强IR诱导的肝癌细胞凋亡 (Molecular Endocrinology, 2011)。3) TR3是异构酶Pin1的新底物。TR3与Pin1结合，其中Ser95-Pro是Pin1提高TR3稳定性的关键位点。Pin1催化ERK2磷酸化的TR3 Ser431-Pro位点异构化，增强TR3转录激活活性。Pin1还通过募集辅激活子促进TR3介导的细胞增殖 (Oncogene, 2011)。4) 顺铂刺激下TR3被Chk2磷酸化。磷酸化增强了TR3蛋白稳定性，同时也促进TR3与BRE和RNF-7启动子结合，抑制这两个抗凋亡基因表达，促进肠癌细胞凋亡 (Carcinogenesis, 2011)。

中文关键词： 孤儿受体TR3;蛋白相互作用;细胞死亡；细胞生长；磷酸化

英文摘要： TR3 is an orphan nuclear receptor. However, its ligand is unknown. TR3 involves in the regulation of cell proliferation and death through protein-protein interaction. In this project, we have demonstrated that 1) TR3 is a negative regulator of canonical Wnt signaling. Ablation of TR3 significantly enhances Wnt signaling activity and the proliferation of intestinal epithelial cells. Loss of TR3 function dramatically increases intestinal tumorigenesis in Apcmin/+ mice, whereas gain of TR3 function in intestinal epithelium decreases intestinal tumor number. TR3 interacts with both βatenin and TCF4. These interactions not only induce the dissociation of βatenin from TCF4 on chromatin but also facilitate the recruitment of co-repressors to the TCF4-binding element in the promoters of Wnt target genes. However, in most clinical colorectal cancers, GSK3βs aberrantly activated and TR3 is hyperphosphorylated, which diminishes TR3's ability to suppress Wnt signaling (Chen et al., Gut, 2011). 2) TR3 interacts with Ku80 and inhibits its binding to DNA ends, which then suppresses DSB repair. On the other hand, TR3 is a phosphorylation substrate for DNA-PK and interacts with DNA-PKcs in a Ku80-independent manner. Phosphorylated TR3, in turn, enhances DNA-PK-induced phosphorylation and p53 transcription activity, thereby enhancing IR-induced apoptosis in hepatoma cells. Therefore, TR3 functions not only in DSB repair regulation but also in IR-induced hepatoma cell apoptosis (Zhao et al., Molecular Endocrinology, 2011). 3) TR3 is a novel substrate for Pin1 (a unique peptidyl-prolyl cis/trans isomerase), and the mitogenic function of TR3 depends on Pin1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that interact with Pin1. The Ser95-Pro motif of TR3 is the key site through which Pin1 enhances TR3 stability by retarding its degradation. Pin1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by ERK2, resulting in enhanced TR3 transactivation. Furthermore, Pin1 not only facilitates TR3 to recruit p300, but also promotes TR3 targeting to the promoter of cyclin D2, thereby inducing cell proliferation (Chen et al., Oncogene, 2011). 4) A novel cross-talk for TR3-mediated cisplatin-induced apoptosis of colon cancer cells. Upon cisplatin stimulation, TR3 is phosphorylated by Chk2. This modification not only stabilizes TR3, but also promotes TR3 binding to its response elements on the promoters of BRE and RNF-7 and suppresses the expression of these two anti-apoptotic genes, thereby contributing to the induction of apoptosis of cancer cells (Yao et al., Carcinogenesis, 2011).

英文关键词： orphan receptor TR3; protein interaction; cell death; cell proliferation; phosphorylation