Development of specific prevention against DNA damage caused by environment
Development of specific prevention against DNA damage caused by environment
批准号:
11557031
负责人:
SAKAI Toshiyuki
金额:
$8.58万
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
1999
资助国家:
日本
项目状态:
已结题
起止时间:
1999 至 2002
中文摘要
gadd 45基因通过p53依赖性或p53非依赖性途径被UV照射转录激活。为了研究参与紫外线照射诱导的gadd 45在一个p53非依赖性途径的序列,我们进行了突变分析的人gadd 45启动子融合的荧光素酶报告基因的细胞系中,p53被灭活。我们发现,UV响应元件参与Oct-1结合位点相对于转录起始位点的-99 bp处。电泳迁移率变动分析表明,Oct-1,转录因子,绑定这个元素上的gadd 45基因,虽然强度和流动性模式的延迟带不改变紫外线照射。这些结果提示Oct-1调控元件可能是紫外线照射激活gadd 45启动子的一个重要元件,而组蛋白去乙酰化酶(HDAC)抑制剂可使多种肿瘤细胞生长停滞于G1期和/或G2/M期,并诱导肿瘤细胞分化和/或凋亡。我们证明,gadd 45,这已被证明是导致细胞周期停滞在G2/M期,并参与遗传毒性应激诱导的细胞凋亡,也是由一个典型的HDAC抑制剂,抑制素A(TSA),通过其启动子在p53非依赖性的方式。为了确定gadd 45启动子的激活机制,我们进行了荧光素酶报告基因分析和电泳迁移率变动分析。对gadd 45启动子的分析表明,Oct-1和CCAAT位点都是TSA完全激活所必需的。我们还发现转录因子Oct-1和NF-Y特异性结合到每个位点。我们的研究结果表明,HDAC抑制剂可以诱导gadd 4S通过其启动子没有功能性p53和Oct-1和NF-Y协调参与TSA诱导的gadd 45启动子的激活。
英文摘要
The gadd45 gene is transcriptionally activated by UV irradiation through p53-dependent or p53-independent pathways. To investigate the sequences involved in induction of gadd45 by UV irradiation in a p53-independent pathway, we performed mutation analyses of the human gadd45 promoter fused to the luciferase reporter gene in cell lines in which p53 was inactivated. We found that the UV-responsive element was involved in the Oct-1 binding site at -99 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that Oct-1, a transcription factor, bound this element on the gadd45 gene, although the intensity and mobility pattern of the retarded bands were not altered by UV irradiation. These results suggest that the Oct-1 regulatory element might be one of the essential elements involved in the activation of the gadd45 promoter by UV irradiation in a p53-indepeadent pathway.Histone deacetylase (HDAC) inhibitors have been revealed to cause growth arrest at G1 and /or G2/M phases, differentiation, and/or apoptosis in a wide variety of tumor cells. We demonstrated that gadd45, which has been shown to cause cell cycle arrest at G2/M phase and take part in genotoxic stress-induced apoptosis, is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and elecrophoretic mobility shift assays. Analysis of the gadd45 promoter revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that transcription factors, Oct-1 and NF-Y, specifically bind to each site. Our results suggest that HDAC inhibitors can induce gadd4S through its promoter without functional p53 and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.
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Evdokiou, A et al.: "Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene"Journal of Molecular Endocrinology. 25. 195-206 (2000)
Evdokiou, A 等人:“人 p21WAF1/CIP1 基因启动子中新型降钙素反应元件的鉴定”《分子内分泌学杂志》。
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Inoue, T et al.: "Sp1 and NF-Y synergistically mediate the effect of vitamin D3 in the p27Kip1 gene promoter that lacks vitamin D response elements"The Journal of Biological Chemistry. 274. 32309-32317 (1999)
Inoue, T 等人:“Sp1 和 NF-Y 协同介导缺乏维生素 D 反应元件的 p27Kip1 基因启动子中维生素 D3 的作用”《生物化学杂志》。
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Sowa, Y., Sakai, T.: "Butyrate as a model for "gene-regulating chemoprevention and chemotherapy""Biofactors. 12. 283-287 (2000)
Sowa, Y., Sakai, T.:“丁酸盐作为“基因调节化学预防和化疗”的模型”生物因子。
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Takahashi, S et al.: "Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation"Cancer Research. 61. 1187-1195 (2001)
Takahashi, S 等人:“gadd45 启动子的 Oct-1 调节元件参与 p53 独立的紫外线照射反应”癌症研究。
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通讯作者:
Huang, L et al.: "Activation of the p21/WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites"Oncogene. 19. 5712-5719 (2000)
Huang, L 等人:“组蛋白脱乙酰酶抑制剂辛二酰苯胺异羟肟酸 (SAHA) 通过 Sp1 位点独立于 p53 激活 p21/WAF1/CIP1 启动子”癌基因。
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共 57 条
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Activation of extrinsic coagulation on tumor cell
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A Study for fusion with Pattern Recognition and Artificial Intelligence in the hierarchical structures
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国内基金
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