L-选择素交联促进白细胞内炎症因子CSF-1基因转录的机制研究

发布时间：2018-01-07 00:46

本文关键词：L-选择素交联促进白细胞内炎症因子CSF-1基因转录的机制研究　出处：《东北师范大学》2008年硕士论文　论文类型：学位论文

【摘要】： L-选择素是选择素家族的一员,组成性的表达在各种类型的白细胞上,它能够介导淋巴细胞的归巢和白细胞向炎症部位的募集,从而在免疫系统中发挥重要的作用。L-选择素不仅可以作为一个粘附分子起到捕获白细胞的作用,还能作为一个信号分子在细胞粘附事件中发挥作用。L-选择素与其单克隆抗体的结合,能引起细胞形态变化,细胞骨架重排,氧呼吸爆发,细胞内IL-8以及TNFα基因的表达上调等。这些研究显示L-选择素交联引起白细胞内的不同信号途径的活化过程可能与不同激酶的活性和核转录因子的活化相关。 c-Abl激酶是一类非受体酪氨酸激酶,对信号转导有重要作用。c-Abl包含催化结构域,脯氨酸富集结构域,SH2和SH3结构域。此外,在C端还包括核输入和核输出信号,F,G-肌动蛋白结合结构域。哺乳动物中c-Abl在核内和胞质中都有分布。核内c-Abl具有转录调节作用,特别是在应答细胞DNA损伤和凋亡时。本文主要探讨了c-Abl分子是否以及如何通过调节集落刺激因子-1(CSF-1)基因的表达来参与由L-选择素交联起始的信号事件。实验结果表明,过表达野生型而不是激酶突变型的c-Abl能够增强由L-选择素交联引起的CSF-1基因的表达。用c-Abl激酶抑制剂处理活化前的细胞则降低了由c-Abl过表达引起的CSF-1基因的表达,说明L-选择素交联引起的CSF-1基因的表达增强依赖于c-Abl的激酶活性。我们发现,L-选择素交联后可以引起c-Abl入核,并且核内的c-Abl磷酸化c-Jun,进而调节AP-1的活性。此后,活化的c-Abl与AP-1结合,在CSF-1的启动子区组成复合物调节L-选择素活化的Jurkat细胞中CSF-1的基因转录。这些结果提示,在L-选择素交联引起的信号事件中,核内c-Abl可以通过调节AP-1的活性调控CSF-1的转录。
[Abstract]:L- selectin is a member of selectin family, constitutively expressed in various types of white blood cells, it can raise the homing mediated lymphocytes and white blood cells to sites of inflammation, which play a role in selecting.L- important elements can be used as an adhesion molecule to capture white blood cells in the immune system also, as a signal molecule plays an important role in.L- binding and selection of monoclonal antibody in cell adhesion events, can cause changes in cell morphology, cytoskeleton, oxygen respiratory burst, intracellular IL-8 and TNF gene expression increased. These studies show that L- selectin cross-linking caused by activation of different signaling pathways in white blood cells may be associated with the activity of nuclear transcription factor and different kinase activation.
C-Abl kinase is a non receptor tyrosine kinase, plays an important role in.C-Abl contains the catalytic domain of signal transduction, the proline rich domain, SH2 domain and SH3. In addition, in the end also includes C nuclear import and nuclear export signal, F, G- and actin binding domain. The distribution of c-Abl in the nucleus in mammals the nucleus and cytoplasm. C-Abl has a role in transcriptional regulation, especially in response to DNA damage and apoptosis of cells.
This paper mainly discusses whether and how c-Abl molecules by regulating the colony-stimulating factor -1 (CSF-1) gene expression in selected by the L- signal events starting crosslinking. The experimental results show that overexpression of wild-type but not mutant kinase c-Abl can enhance the expression of CSF-1 gene induced by L- selectin cross-linking. With c-Abl kinase inhibitor treatment before activation of cells decreased by c-Abl overexpression of CSF-1 gene caused, enhanced c-Abl dependent kinase activity and CSF-1 gene expression of L- selectin induced crosslinking. We found that the L- element selection after crosslinking can cause nuclear translocation of c-Abl, c-Abl and phosphorylated c-Jun in the nucleus thus, regulating the activity of AP-1. Then, c-Abl and AP-1 activated with CSF-1 gene transcription in the promoter region of the composition of the CSF-1 complex regulates L- selectin activation of Jurkat cells. These results provided In the signal events caused by L- selectin crosslinking, the c-Abl in the nucleus can regulate the transcription of CSF-1 by regulating the activity of AP-1.

【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2008
【分类号】：R363

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