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组蛋白去乙酰化酶抑制剂诱导H eLa细胞p21^WAF1/CIP1表达的分子机制研究

Molecular mechanism of p21^WAF1/CIP1 expression induced by histone deacetylase inhibitors in HeLa cell line

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【Author】 ZHAO Guo-Wei~(2),SONG Yi~(1),DONG Yan~(1),QIAN Jun-Jie~(1),MEI Zhu-Zhong~(1),TIAN Bao-Lei~(1),ZHANG Ying-Jiu~(2),SUN Zhi-Xian~(1)(1.Institute of Radiation Medicine,Academy of Military Medical Sciences,Beijing 100850,China;2.College of Life Science,Jilin University,Changchun 130021,China) Objective:To investigate the molecular mechanism of histone deacetylase inhibitors(HDIs) in cell cycle arrest and induction of p21~(WAF1/CIP1).Methods: Human cervix carcinoma HeLa cells were used as models.Cells were treated with trichostatin A(TSA),a typical kind of HDIs,and analyzed by flow cytometry,Western blot,RT-PCR and Dual-Luciferase Reporter Assay System.Results and Conclusion: Results showed that TSA could induce G_1 and G_2 arrest in HeLa cells,and significant apoptosis could be detected with increased dose and longer time.In the meantime, the mRNA expression of p21~(WAF1/CIP1) could be induced,which could indicate the extent of cell cycle arrest.Luciferase assays revealed that TSA response elements locate at the p21~(WAF1/CIP1)promoter GC-enriched sites proximal to the transcriptional start site,and tumor repressor p53 which was also induced by TSA was probably involved in the transactivation of p21~(WAF1/CIP1) promoter.

【机构】吉林大学生命科学学院；军事医学科学院放射与辐射医学研究所；军事医学科学院放射与辐射医学研究所长春130021；北京100850；长春130021；北京100850；

【摘要】目的:研究组蛋白去乙酰化酶抑制剂(HD Is)诱导肿瘤细胞产生周期阻滞以及诱导p21WAF1/C IP1表达的分子机制。方法:以人宫颈癌HeLa细胞为模型,用曲古抑菌素A(TSA)处理HeLa细胞,通过流式细胞术检测细胞周期及凋亡,通过W estern印迹及RT-PCR检测周期相关分子的蛋白及mRNA的表达;并构建TSA靶分子启动子区的荧光素酶报告质粒,进一步检测TSA的主要作用位点,寻找相关作用途径。结果与结论:TSA可诱导HeLa细胞发生周期阻滞,并呈现明显的剂量和时间依赖关系,加大用药剂量及延长用药时间可诱导凋亡。TSA可显著诱导p21WAF1/C IP1的表达,表现为转录水平的调节,其变化可以指示周期阻滞的程度。p21WAF1/C IP1启动子区3′端是TSA作用的主要位点,同样被TSA诱导表达增加的p53很可能通过与其效应元件的结合而使TSA诱导p21WAF1/C IP1表达的总效果增强。更多还原

【Abstract】 Objective:To investigate the molecu larm echan ism of h istone deacetylase inh ib itors(HD Is) in cell cyc le ar-rest and induction of p21WAF1 /C IP1.M ethod s:Hum an cervix carc inom a HeLa cells were used as models.Cells were treated w ith trichostatin A(TSA),a typ ical k ind ofHD Is,and analyzed by flow cytom etry,W estern b lot,RT-PCR and Dual-Luc if-erase Reporter Assay System.R esu lts and C onc lu sion:Resu lts showed that TSA cou ld induce G1and G2arrest in HeLa cells,and sign ificant apoptosis cou ld be detected w ith increased dose and longer tim e.In the m eantim e,the mRNA expres-sion of p21WAF1 /C IP1cou ld be induced,wh ich cou ld ind icate the extent of cell cyc le arrest.Luc iferase assays revealed that TSA response elem ents locate at the p21WAF1 /C IP1promoter GC-enriched sites proxim al to the transcriptional start site,and tumor repressor p53 wh ich was also induced by TSA was probab ly involved in the transactivation of p21WAF1 /C IP1promoter.更多还原

【关键词】组蛋白去乙酰化酶抑制剂；曲古抑菌素A； p21WAF1/CIP1沉默；细胞周期阻滞； p53；基因表达调控； Hela细胞；
【Key words】 histone deacetylase inhibitors； TSA； p21^WAF1/CIP1 silence； cell cycle arrest； p53； gene expression regulation； Hela cell；

【基金】国家自然科学基金资助项目(No.30370329)

【文献出处】军事医学科学院院刊 ,Bulletin of The Academy of Military(Medical Sciences) , 编辑部邮箱 ,2005年05期

【分类号】Q753;
【被引频次】2
【下载频次】205

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组蛋白去乙酰化酶抑制剂诱导H eLa细胞p21WAF1/CIP1表达的分子机制研究

Molecular mechanism of p21WAF1/CIP1 expression induced by histone deacetylase inhibitors in HeLa cell line

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组蛋白去乙酰化酶抑制剂诱导H eLa细胞p21^WAF1/CIP1表达的分子机制研究

Molecular mechanism of p21^WAF1/CIP1 expression induced by histone deacetylase inhibitors in HeLa cell line