一种新型造血相关转录调节因子EDAG的功能及作用机制研究

发布时间：2018-04-14 05:02

本文选题：EDAG + NF-κB　；参考：《中国人民解放军军事医学科学院》2005年博士论文

【摘要】：EDAG是我们实验室自行分离克隆的一种特异表达于造血组织和细胞的新基因。前期研究表明EDAG可促进造血细胞的增殖并抑制分化,并且具有转化活性,提示其可能参与造血发育调控及白血病的发生。本研究对EDAG功能进行了深入研究。首先,EDAG在IL-3依赖细胞株Ba/F3中的过表达,可使细胞在IL-3撤除条件下存活增多,细胞抗凋亡能力增强并伴随多种抗凋亡相关蛋白表达的上调;其中NF-κB的活化是EDAG促使细胞抗凋亡能力增强的主要原因,P13K通路参与了EDAG对NF-κB的活化过程。其次,利用CD11a启动子制备了EDAG特异表达于造血细胞的转基因小鼠,并对小鼠的表型进行了全面分析。发现EDAG在小鼠造血细胞中的过表达影响了多种类型造血细胞的发育与分化,主要表现为:小鼠髓系造血增强,出现骨髓增生性疾病特征:T、B淋巴细胞发育受阻;造血干细胞数量增多,分化能力下降;DC细胞比例增多等。分析还发现转基因小鼠骨髓细胞中多种造血相关基因的表达发生改变。该结果表明EDAG是造血调控过程中的关键调节分子。利用酵母及哺乳动物系统发现EDAG具有转录激活活性,EDAG相互作用蛋白THAP11及蛋白激酶C(PKC)激活剂PMA对EDAG的转录活性具有明显的增强作用。基于THAP11是一种DNA结合蛋白,我们认为EDAG/THAP11相互作用可能形成一种新型转录调节复合物,磷酸化修饰可能是其发挥转录调节活性的重要调节方式。综合以上结果,我们认为:EDAG基因是一种新型转录调节因子,参与了造血细胞凋亡与造血系统发育的调控。
[Abstract]:EDAG is a new gene cloned by our laboratory specifically expressed in hematopoietic tissues and cells. Previous studies showed that EDAG can promote the proliferation of hematopoietic cells and inhibit the differentiation, and has transforming activity, suggesting that it may participate in the regulation of hematopoietic development and the occurrence of leukemia. This study conducted in-depth research on the function of EDAG. First of all, EDAG dependent cell line Ba/F3 overexpression in IL-3, the cells in the removal of IL-3 under the condition of survival increased, the anti apoptosis ability of cells and enhance the expression of anti apoptosis protein with various increases; the activation of NF- kappa B EDAG is the main reason for the cells to enhance the anti apoptosis ability, P13K pathway is involved in the activation process of EDAG the NF- K B. Secondly, the preparation of transgenic mouse promoter specific expression of EDAG in hematopoietic cells by CD11a, and the phenotype of mice were analyzed. EDAG was found in mice Over expression of hematopoietic cells influence the development and differentiation of various types of hematopoietic cells, mainly as follows: mouse myeloid hematopoietic enhancement, appear myeloproliferative disease characteristics: T, B lymphocyte development blocked; hematopoietic stem cell number and differentiation ability; the proportion of DC cells increased. The analysis also found that the expression of a variety of bone marrow hematopoietic cell related genes in transgenic mice changed. The results show that EDAG is a key regulator in the hematopoiesis. It is found that EDAG has transcriptional activation activity by yeast and mammalian systems, EDAG interacts with the THAP11 protein and protein kinase C (PKC) activation of transcription activator PMA on EDAG is greatly enhanced. Based on THAP11 is a DNA binding protein, we believe that EDAG/THAP11 interactions may form a new kind of transcription complexes, phosphorylation may play its transcriptional regulation An important mode of regulation of the activity of the ganglion.
In combination with the above results, we think that the EDAG gene is a new type of transcriptional regulator and participates in the regulation of hematopoietic cell apoptosis and hematopoietic system development.

【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2005
【分类号】：Q78

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