中南大学肿瘤研究所
国家留学基金委高水平项目资助, 加拿大卫生研究院(CIHR)研究基金资助项目, 国家重点基础研究发展计划项目 (2011CB9107040)和国家自然科学基金(30973289, 81272971)资助项目
Cancer Research Institute , Central South University
This work was supported by grants from RG is an awardee of The Chinese Scholarship Council (CSC). This work was partially supported by grants from The Canadian Institutes of Health Research to JH, The National Basic Research Program of China (2011CB9107040) and The National Natural Science Foundation of China (30973289, 81272971)
ZNF403和LCRG1是人类基因ZNF403的2个不同转录剪切本.以往的研究表明LCRG1在喉癌细胞株Hep-2中具有抑瘤特性.本研究旨在探明ZNF403和LCRG1不同剪切本之间的关系以及在肿瘤细胞中对ZNF403的功能进行研究.首先,采用实时荧光定量PCR对这2个转录本的相对表达水平进行分析,结果表明,ZNF403表达水平在不同细胞株中明显高于LCRG1(>10倍),为该基因的主要转录表达产物.随后分别采用MTT细胞生长分析法和裸鼠体内成瘤实验在体外和体内对ZNF403的功能进行分析,结果显示ZNF403的基因沉默可以同时在体内和体外抑制喉癌细胞Hep-2细胞的生长.为了探明其作用机制,本研究还采用细胞信息学、流式细胞周期分析术和高通量PCR点阵分析方法进一步分析,结果表明,ZNF403的基因沉默可显著抑制细胞DNA的复制并延缓细胞周期进入到有丝分裂期.同时发现ZNF403可调节一系列的细胞周期调节蛋白如MCM2、p21、ATM、MRE11A等.综上研究提示ZNF403为一新的细胞周期调节因子,其功能的缺失与肿瘤发生发展密切相关.
ZNF403 and LCRG1 are two alternative splicing isoforms from human gene ZNF403. Previous study shows that LCRG1 displays tumor-suppressive properties in laryngeal carcinoma cell line Hep-2 cells. The aim of this study is to clarify the relationships between these two isoforms and further investigate the role of ZNF403 in tumor cells. Realtime PCR analysis was first applied to demonstrate the relative abundance of these two isoforms and showed that ZNF403 is the major transcription product. The function of ZNF403 in cell growth was next accessed by MTT assay and tumor growth in nude mice analysis, respectively. The results indicated that ZNF403 knockdown resulted in inhibition of cell growth in Hep-2 cell both in vitro and in vivo. Moreover, bioinformatics analysis, flow-cytometric analysis and PCR array analysis were performed to elucidate the mechanism under the role of ZNF403 in cell growth. Knockdown of ZNF403 significantly decreased the rate of DNA synthesis and mitosis. Additionally, a number of key cell-cycle regulating components such as MCM2, p21, ATM and MRE11A were identified to be mediated by ZNF403. Altogether, our findings suggest that ZNF403 is a novel cell cycle regulator, which may play an essential role in tumorigenesis.
关瑞,侯德富,饶 翔,关勇军,欧阳咏梅,余艳辉,Jim HU,陈主初. ZNF403,一个新的细胞周期调节因子的功能研究[J].生物化学与生物物理进展,2013,40(2):147-158
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