E3泛素连接酶TRIM21在结肠炎以及结肠癌中的作用与机制

发布时间：2018-06-17 05:29

本文选题：TRIM21 + β-连环蛋白　；参考：《华东师范大学》2017年硕士论文

【摘要】：结肠炎是一种由多种因素诱发的造成肠道上皮损伤和炎症的常见肠道疾病,结肠炎发生之后,肠道上皮细胞的增殖对于损伤部位的修复尤为重要;长期的慢性结肠炎,可能导致肠上皮细胞的恶性增殖,并逐步发展成结肠癌。TRIM21是一种E3泛素连接酶,最初是在系统性红斑狼疮中发现的一种蛋白质,参与系统性红斑狼疮的病发,而临床研究表明系统性红斑狼疮与结肠炎的发生密切相关。然而,TRIM21在结肠炎中的功能尚无报道。本研究通过构建DSS诱导的结肠炎模型,发现TRIM21在结肠炎中的表达显著上调。利用TRIM21的基因缺失小鼠,我们证明TRIM21缺失之后能增强机体对结肠炎的抵抗性,TRIM21缺失之后小鼠体重减轻程度更少、存活率得到显著提高。此后,我们通过构建嵌合体小鼠证明了 TRIM21主要是在肠上皮细胞中参与调节结肠炎的发生。进一步研究表明,TRIM21能与β-catenin结合并促使其发生K48位形式的泛素化,从而被蛋白酶体所降解。与WT小鼠相比,TRIM21缺失小鼠中1-catenin在肠上皮细胞中的蛋白表达水平显著增强,同时β-catenin的靶基因CycIinD1表达量也上升,肠上皮细胞的增殖明显增加。另外,我们发现TRIM21在人肠癌中的表达显著降低,利用AOM/DSS诱导小鼠结肠癌发现,与WT小鼠相比,TRIIM21缺失小鼠结肠癌的发生更为明显。同时,我们发现TRIM21在肠炎与肠癌中的表达与IFN-γ相关,IFN-y可以在肠上皮细胞中诱导TRIM21表达,在结肠炎中IFN-y是上调表达的,而在结肠癌中IFN-γ是下调,因此导致TRIM21在结肠炎中高表达,在结肠癌中低表达。综上所述,我们发现了 TRIM21在肠炎中高表达,在肠癌中低表达。TRIM21在肠上皮细胞中能通过泛素化降解β-catenin,从而抑制细胞增殖。本研究揭示了TRIM21在结肠炎以及结肠癌发病中的作用及机制,为结肠炎以及结肠癌的发病机理提供了新的理论依据,也为针对结肠炎以及结肠癌的药物开发提供了潜在的靶点。
[Abstract]:Colitis is a common intestinal disease induced by many factors. After colitis occurs, the proliferation of intestinal epithelial cells is particularly important for the repair of injury sites; chronic colitis, chronic colitis, It may lead to the malignant proliferation of intestinal epithelial cells and develop into colon cancer. TRIM21 is an E3 ubiquitin ligase, originally found in systemic lupus erythematosus, a protein involved in the pathogenesis of systemic lupus erythematosus. Clinical studies have shown that systemic lupus erythematosus is closely related to the occurrence of colitis. However, the function of TRIM21 in colitis has not been reported. In this study, DSS induced colitis model was constructed and the expression of TRIM21 was significantly up-regulated in colitis. Using TRIM21 gene deletion mice, we demonstrated that TRIM21 deletion can enhance the body resistance to colitis after TRIM21 deletion mice weight loss is less, the survival rate is significantly improved. Since then, we have demonstrated that TRIM21 is involved in the regulation of colitis mainly in intestinal epithelial cells by constructing chimeric mice. Further studies showed that TRIM21 could bind to 尾 -catenin and induce Ubiquidization in the form of K48, which was degraded by proteasome. Compared with WT mice, the expression of 1-catenin protein in intestinal epithelial cells was significantly increased in TRIM21 deficient mice, and the expression of 尾 -catenin target gene CycIin D1 was also increased, and the proliferation of intestinal epithelial cells was increased. In addition, we found that the expression of TRIM21 was significantly decreased in human colorectal cancer, and the colon cancer in mice induced by AOM / DSS was more obvious than that in WT mice. At the same time, we found that the expression of TRIM21 in enteritis and colorectal cancer was induced by IFN- 纬 -associated IFN-y in intestinal epithelial cells, IFN-y was up-regulated in colitis, and IFN- 纬 was down-regulated in colon cancer, which resulted in high expression of trimim 21 in colitis. Low expression in colon cancer. In conclusion, we found that TRIM21 is highly expressed in enteritis, and that TRIM21 can degrade 尾 -catenin by ubiquitin in intestinal epithelial cells, thus inhibiting cell proliferation. This study revealed the role and mechanism of TRIM21 in the pathogenesis of colitis and colon cancer, provided a new theoretical basis for the pathogenesis of colitis and colon cancer, and provided a potential target for the development of drugs for colitis and colon cancer.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R574.62;R735.35

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