【作者】 王昕；

【导师】 樊飞跃；

【作者基本信息】 北京协和医学院 ， 放射医学， 2011， 博士

【摘要】 p53是一种非常重要的抑癌基因,在化学药物、电离辐射等作用下,p53通过应激通路,可诱导细胞生长阻滞,细胞凋亡,细胞分化以及DNA修复。在p53缺失或者失活时,细胞周期无法停滞,无法启动细胞凋亡,细胞会出现癌变。肿瘤抑制基因p53基因突变是人类癌症中最常见的基因组改变。野生型p53基因的控制中发挥重要作用细胞周期和诱导细胞凋亡。将野生型p53基因或p53蛋白介导入到肿瘤细胞是一种有效的用于人类癌症治疗策略。本文回顾了p53的特点,研究阶段,作用机制和p53肿瘤抑制因子在人类癌症中的研究进展。septin是一个广泛存在于除植物以外所有真核生物中的基因家族。最初认为septin家族是与酵母细胞胞质分裂相关的基因家族。近年来,这一家族的—些成员与肿瘤发生、神经功能障碍和病原微生物感染的过程直接相关。septin家族的功能研究正逐步成为细胞生物学及病理学研究的新热点。在本课题的研究中,我们观察到,p53能够通过对紫外照射的应激通路,最终影响septin 2磷酸化的水平,而septin 2磷酸化水平的升高,能够增加septin 2、6、7复合物的稳定性,进而增加肌动蛋白微丝的稳定性,使得胞质分裂能够顺利进行。而让我们惊奇的发现,同样在紫外照射下,septin 2磷酸化水平的改变,能够影响p53 ser15位点的磷酸化水平,进而达到抑制p53蛋白活性和稳定性的结果。这种p53磷酸化septin 2及septin 2对于p53的负反馈作用的环状调节关系,对于影响有丝分裂的胞质分裂和p53的活性及稳定性有着重要意义。综上所述,本文研究了p53对septin 2的磷酸化作用,并探讨了septin 2对p53的负反馈调节,为深入研究p53的下游信号通路和septin 2蛋白家族的功能作用提供了理论基础。更多还原

【Abstract】 The tumor suppressor gene p53 is a transcription factor which mediates several cellular processes including growth arrest,apoptosis,differentiation, and DNA damage repair. In the absence or inactivation of p53, the cell cycle can not be stagnant and unable to prepare for apoptosis, so the cells appear cancerous. Mutation in the tumor suppressor gene p53 has been turned out to be the most common genomic variation in human cancer.Wild-type p53 gene play an important role in the control of cell cycle and induction of apoptosis. Introducting exogenous wild-type p53 gene or p53 protein into tumor cell is a potent therapeutic strategy for human cancer. The present paper reviews the characteristic, research progress and mechanism of tumor suppressor gene p53 in human cancer.The septins are a family of proteins which are broadly distributed in almost all of eukaryotes except plants. Septin was first identified in yeast as a protein that played a role in cytokinesis. Recently, some septin family members participate in the pathogenesis of different diseases including neoplasia, neurodegeneration and infections. These make the research of septins a hallmark in cell biology and pathology.In our research, we observed p53 affect the level of phosphorylation of septin 2 after UV radiation through the stress pathway. The stability of septin2,6,7 complex is enhancive as septin 2 phosphorylation increased, thus increasing the stability of actin filaments, making cytokinesis division successfully. We’re interested in finding that septin 2 phosphorylation level changing can influence p53 ser15 phosphorylation site after UV irradiation, and then to inhibit p53 protein activity and reduce its stability. This reaction between p53 and septin2 is important to the regulation of cytokinesis through changing activity and stability of p53.Taken together, it is one of the mechanisms for septin 2 being regulated by p53 and involving in the process of cytokinesis. Through the research work, we hope to provide some theoretical principle to intensively explain the process between the signaling pathways of p53 downstream and the function of septin 2 protein.更多还原