Differentiation of DNA reactive and non-reactive genotoxic mechanisms using gene expression profile analysis
Differentiation of DNA reactive and non-reactive genotoxic mechanisms using gene expression profile analysis
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DOI：
10.1016/j.mrfmmm.2004.01.009
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发表时间：
2004-05-15
影响因子：
2.3
通讯作者：
Aubrecht, J
中科院分区：
文献类型：
--
作者：
Dickinson, DA;Warnes, GR;Aubrecht, J
基因毒性应激引发多种生物反应，包括调节DNA修复、细胞存活和细胞死亡的基因的转录激活。在这里，我们研究了基因表达谱是否可以区分DNA反应性和DNA非反应性遗传毒性机制。我们分析了顺铂和氯化钠处理的L5178Y细胞的基因表达谱和微核水平。对顺铂遗传毒性（微核数量增加6倍）和基因表达谱（基因毒性应激相关基因表达增加）的评估与顺铂作为DNA加合物形成剂的作用模式一致。顺铂处理细胞的基因表达谱分析确定了许多mRNA表达的强调控基因，包括与DNA损伤相关的基因（即GADD45家族成员）、早期反应（即cFOS）和热休克蛋白（即HSP40同系物）。通过DNA-蛋白交联和铂-DNA结合测量，基因表达变化与DNA损伤密切相关。区分顺铂基因毒性应激相关表达谱与一般毒性应激。我们比较了顺铂处理的细胞与氯化钠处理的细胞的基因表达谱，氯化钠会导致渗透休克和细胞裂解。虽然氯化钠处理引起微核的双重诱导，但等量浓度下的基因表达谱与顺铂观察到的谱明显不同。氯化钠的特征是与DNA损伤和修复相关的基因完全缺乏表达变化。在总结。基因表达谱清楚地区分了顺铂和氯化钠的DNA反应性和非反应性遗传毒性机制。本研究结果提示基因表达谱分析在阐明基因毒性药物作用机制方面具有潜在的实用价值。(C) 2004 Elsevier B.V.版权所有
Genotoxic stress triggers a variety of biological responses including the transcriptional activation of genes regulating DNA repair, cell survival and cell death. Here, we investigated whether gene expression profiles can differentiate between DNA reactive and DNA non-reactive mechanisms of genotoxicity. We analyzed gene expression profiles and micronucleus levels in L5178Y cells treated with cisplatin and sodium chloride. The assessment of cisplatin genotoxicity (up to six-fold increase in the number of micronuclei) and gene expression profile (increased expression of genotoxtic stress-associated genes) was in agreement with cisplatin mode of action as a DNA adduct-forming agent. The gene expression profile analysis of cisplatin-treated cells identified a number of genes with robust up regulation of mRNA expression including genes associated with DNA damage (i.e. members of GADD45 family), early response (i.e. cFOS), and heat shock protein (i.e. HSP40 homologue). The gene expression changes correlated well with DNA damage as measured by DNA-protein crosslinks and platinum-DNA binding. To differentiate the genotoxic stress-associated expression profile of cisplatin from a General toxic stress. we have compared the gene expression profile of cisplatin-treated cells to cells treated with sodium chloride, which causes osmotic shock and cell lysis. Although the sodium chloride treatment caused a two-fold induction of micronuclei, the gene expression profile at equitoxic Concentrations was remarkably distinct from the profile observed with cisplatin. The profile of sodium chloride featured a complete lack of expression changes in genes associated with DNA damage and repair. In summary. the gene expression profiles clearly distinguished between DNA reactive and non-reactive genotoxic mechanisms of cisplatin and sodium chloride. Our results Suggest the potential utility of gene expression profile analysis for elucidating mechanism of action of genotoxic agents. (C) 2004 Elsevier B.V. All rights reserved.