E3泛素连接酶FBW7对BCL6的调节机制及其在生发中心的作用
发布时间：2018-12-11 02:28
【摘要】：转录抑制因子Bcl6对B细胞生发中心的发育和功能维持起着重要的作用,Bcl6的表达失控将会直接导致B细胞淋巴瘤的产生,因此如何精确调控Bcl6在生发中心中的表达对于预防由生发中心引发的疾病有着重要的意义。大量的研究揭示了 Bcl6的转录水平调控,然而关于Bcl6蛋白翻译后的修饰却鲜为人知。本文中,我们发现了近年来被广泛报道的一种重要的肿瘤抑制因子Fbw7,通过形成SCFFbw7复合体介导Bcl6蛋白的降解,从而控制细胞内Bcl6蛋白稳定性。在本文的研究中,我们通过生物信息学的方法,对Fbw7的底物进行预测,我们发现Bcl6中包含了Fbw7直接识别的降解信号序列,且该段序列在不同物种中高度保守。接下来,我们利用生物化学与分子生物学等技术手段,通过一系列外源和内源的实验验证了 Fbw7能够结合Bcl6并介导其泛素化降解,此外,我们还发现Bcl6的降解依赖于磷酸激酶JNK对其磷酸化。最后,我们进一步探究了Fbw7介导Bcl6降解的生理意义,我们首先发现Fbw7在生发中心B细胞中高表达,当在生发中心中特异性敲除Fbw7基因后,我们观察到生发中心b细胞的发育并未受到影响,然而其抗体类型转换能力却显著受损。初步实验结果发现Fbw7敲除后,生发中心中记忆细胞的比例上调,这可能是Bcl6蛋白水平的上调抑制了 blimpl蛋白,从而导致生发中心b细胞向记忆细胞分化。综上所述,我们的研究发现了 Fbw7通过介导Bcl6的降解,影响生发中心B细胞向记忆细胞的分化来实现对生发中心的调控。
[Abstract]:Transcription suppressor Bcl6 plays an important role in the development and functional maintenance of germinal center of B cells. The uncontrolled expression of Bcl6 will directly lead to the production of B cell lymphoma. Therefore, how to accurately regulate the expression of Bcl6 in germinal centers is of great significance for the prevention of germinal center-induced diseases. A large number of studies have revealed the transcriptional regulation of Bcl6, but little is known about post-translational modification of Bcl6 proteins. In this paper, we have found that Fbw7, an important tumor suppressor, has been widely reported in recent years to control the stability of Bcl6 protein by forming SCFFbw7 complex to mediate the degradation of Bcl6 protein. In this study, we predicted the substrate of Fbw7 by bioinformatics. We found that Bcl6 contains degradation signal sequence recognized directly by Fbw7, and this sequence is highly conserved in different species. Then, by means of biochemistry and molecular biology, we proved that Fbw7 can bind to Bcl6 and mediate its ubiquitin degradation through a series of exogenous and endogenous experiments. We also found that Bcl6 degradation depends on phosphorylation of phosphokinase JNK. Finally, we further explored the physiological significance of Bcl6 degradation mediated by Fbw7. We first found that Fbw7 is highly expressed in germinal center B cells, and when Fbw7 gene is specifically knocked out in germinal center, We observed that the development of germinal center b cells was not affected, but the ability of antibody type conversion was significantly impaired. The preliminary results showed that the proportion of memory cells in germinal center increased after Fbw7 knockout. This may be because the up-regulation of Bcl6 protein level inhibited blimpl protein, which led to the differentiation of germinal center b cells into memory cells. In conclusion, we found that Fbw7 regulates germinal center by mediating the degradation of Bcl6 and affecting the differentiation of germinal center B cells into memory cells.
【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】：Q78
[Abstract]:Transcription suppressor Bcl6 plays an important role in the development and functional maintenance of germinal center of B cells. The uncontrolled expression of Bcl6 will directly lead to the production of B cell lymphoma. Therefore, how to accurately regulate the expression of Bcl6 in germinal centers is of great significance for the prevention of germinal center-induced diseases. A large number of studies have revealed the transcriptional regulation of Bcl6, but little is known about post-translational modification of Bcl6 proteins. In this paper, we have found that Fbw7, an important tumor suppressor, has been widely reported in recent years to control the stability of Bcl6 protein by forming SCFFbw7 complex to mediate the degradation of Bcl6 protein. In this study, we predicted the substrate of Fbw7 by bioinformatics. We found that Bcl6 contains degradation signal sequence recognized directly by Fbw7, and this sequence is highly conserved in different species. Then, by means of biochemistry and molecular biology, we proved that Fbw7 can bind to Bcl6 and mediate its ubiquitin degradation through a series of exogenous and endogenous experiments. We also found that Bcl6 degradation depends on phosphorylation of phosphokinase JNK. Finally, we further explored the physiological significance of Bcl6 degradation mediated by Fbw7. We first found that Fbw7 is highly expressed in germinal center B cells, and when Fbw7 gene is specifically knocked out in germinal center, We observed that the development of germinal center b cells was not affected, but the ability of antibody type conversion was significantly impaired. The preliminary results showed that the proportion of memory cells in germinal center increased after Fbw7 knockout. This may be because the up-regulation of Bcl6 protein level inhibited blimpl protein, which led to the differentiation of germinal center b cells into memory cells. In conclusion, we found that Fbw7 regulates germinal center by mediating the degradation of Bcl6 and affecting the differentiation of germinal center B cells into memory cells.
【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】：Q78
【相似文献】
相关期刊论文 前4条
1 葛振华,黄守雄,周凡,武一曼,王若愚;生发中心淋巴细胞凋亡与小结树突细胞关系的研究[J];解剖学报;1999年02期
2 杨刚;生发中心[J];中国医学科学院学报;2003年01期
3 赵义,王艳华,李在连;生发中心的研究进展[J];国外医学(免疫学分册);1999年06期
4 葛振华;王若愚;李白桦;万集今;;人体淋巴结和扁桃体生发中心内B淋巴细胞免疫细胞化学的研究[J];解剖学报;1991年S1期
相关会议论文 前3条
1 毛洁;毛峥嵘;周韧;金梅;任国平;丁伟;赵菁;;DLBCL中IgVH基因分子特征的初步研究[A];2012年浙江省病理学学术年会论文集[C];2012年
2 欧阳斌q，
本文编号：2371689
本文链接：https://www.wllwen.com/shoufeilunwen/benkebiyelunwen/2371689.html
