Mutagenesis of p53 by reactive PAH and ROS
反应性 PAH 和 ROS 对 p53 的诱变
基本信息
- 批准号:7471955
- 负责人:
- 金额:$ 31.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-08 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:8-Oxo-2&apos-DeoxyguanosineA549AdenineAromatic HydrocarbonsAromatic Polycyclic HydrocarbonsBindingBiological AssayCarcinogensCationsCell LineCellsCharacteristicsCodeCodon NucleotidesColorCultured CellsDNADNA AdductionDNA AdductsDNA DamageDNA lesionDataEnvironmental Air PollutantsEnvironmental PollutantsEpithelial CellsEpoxy CompoundsEventExposure toFossil FuelsFrequenciesGanciclovirGenetic TranscriptionGlycolHSV-Tk GeneHumanIn SituIn VitroInheritedKnock-outLeadLesionLigationLocationLungLung AdenocarcinomaMalignant neoplasm of lungMammalian CellMapsMediatingMetabolic ActivationMetabolic PathwayMethodsModelingMutagenesisMutagensMutateMutationMutation SpectraOGG1 geneOncogenesOxidation-ReductionPathway interactionsPatternPharmaceutical PreparationsPolycyclic HydrocarbonsPolymerase Chain ReactionProtein p53Public HealthQuinonesReactive Oxygen SpeciesRelative (related person)ReporterReporter GenesResearchResistanceRisk FactorsRoleRouteScoreSiteStagingSystemTK GeneTP53 geneTechniquesTestingTobaccoTranscription-Coupled RepairTranscriptional ActivationYeastsadductbasebenzoquinonecarcinogenesiscell killingcigarette smokingdesigngene repairgenetic selectionlung carcinogenesismutantnovelpreferencepromoterrepairedresearch study
项目摘要
DESCRIPTION (provided by applicant):
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental air pollutants that result from fossil fuel combustion and cigarette smoking. PAH exposure is a major risk factor in human lung carcinogenesis. A critical step in multi-stage carcinogenesis is the mutagenic event that results from the formation of DNA adducts. There are three principle routes of metabolic activation of PAH resulting in the formation of diol- epoxides, radical cations, or reactive and redox-active o-quinones. Each of these reactive metabolites have the potential to form DNA-adducts and these adducts may lead to mutation. We are using two approaches to model PAH carcinogenesis, a highly versatile yeast system and human lung cell lines. In lung cancer, the gene most often mutated is p53 where three distinguishing characteristics are found in lung cancer. (1) The pattern of mutations is dominated by G to T transversions; (2) The spectrum of mutations reveals hotspot codons, a few of which are unique to lung cancer; (3) The pattern and spectrum of mutations show a strand bias for mutations on the non-transcribed strand. Our systems use genetic selection methods so that change-in- function mutations can be detected with ease. The yeast reporter system for p53 relies on wild-type p53 binding to a promoter to drive an adenine reporter causing mutant colonies turn red. Our preliminary data suggest that PAH o-quinones, when permitted to undergo redox-cycling, generate 8-oxo-dGuo to cause predominantly G to T transversions with a modest, but significant, preference for hotspots but with no strand bias. We recently devised a system to detect mutations in human lung cells using a p53 dependent promoter to direct transcription of the Herpes TK gene. In this system p53+ cells are killed by exposure to ganciclovir while p53 cells are resistant. The mutant p53 is next rescued from the cells using the yeast system and then sequenced. Using these assays to model p53 mutagenesis we will: (1) Determine the role of repair genes on p53 mutagenesis and compare different PAH metabolites, (2) Map the locations of PAH induced DNA lesions in the p53 gene(3) determine if PAH-metabolites can mutate p53 in lung cells. Our hypothesis is that PAH o- quinones and the ROS they generate provide a route to the p53 mutations found in lung cancer. PUBLIC HEALTH RELEVANCE: Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental air pollutants that result from fossil fuel combustion and cigarette smoking. PAH exposure is a major risk factor in human lung carcinogenesis. This proposal will study the mutagenesis of the p53 oncogene by PAH and their metabolites.
描述(由申请人提供):
多环芳烃(PAH)是普遍存在的环境空气污染物,由化石燃料燃烧和吸烟引起。多环芳烃暴露是人类肺癌发生的主要危险因素。多阶段致癌作用中的关键步骤是DNA加合物形成导致的诱变事件。PAH的代谢活化有三种主要途径,导致形成二醇环氧化物、自由基阳离子或反应性和氧化还原活性的邻醌。这些反应性代谢物中的每一种都有形成DNA加合物的潜力,这些加合物可能导致突变。我们正在使用两种方法来模拟PAH致癌作用,一个高度通用的酵母系统和人类肺细胞系。在肺癌中,最常突变的基因是p53,其中在肺癌中发现了三个显著特征。(1)突变模式主要由G至T颠换主导;(2)突变谱揭示了热点密码子,其中一些是肺癌特有的;(3)突变模式和突变谱显示出非转录链突变的链偏好。我们的系统使用遗传选择方法,以便可以轻松检测功能突变的变化。p53的酵母报告系统依赖于野生型p53与启动子的结合,以驱动腺嘌呤报告基因,导致突变菌落变红。我们的初步数据表明,PAH邻醌,当允许进行氧化还原循环,产生8-oxo-dGuo主要导致G到T颠换与适度的,但显着的,热点的偏好,但没有链的偏见。我们最近设计了一个系统来检测突变的人肺细胞使用p53依赖性启动子,以指导疱疹病毒TK基因的转录。在该系统中,p53+细胞通过暴露于更昔洛韦而被杀死,而p53细胞具有抗性。然后使用酵母系统从细胞中拯救突变型p53,然后测序。使用这些试验来模拟p53突变,我们将:(1)确定修复基因对p53突变的作用,并比较不同的PAH代谢物,(2)绘制PAH诱导的DNA损伤在p53基因中的位置(3)确定PAH代谢物是否可以突变肺细胞中的p53。我们的假设是PAH邻醌和它们产生的ROS为肺癌中发现的p53突变提供了一条途径。公共卫生相关性:多环芳烃(PAH)是普遍存在的环境空气污染物,由化石燃料燃烧和吸烟引起。多环芳烃暴露是人类肺癌发生的主要危险因素。本研究拟探讨PAH及其代谢产物对p53癌基因的致突变作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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JEFFREY M FIELD其他文献
JEFFREY M FIELD的其他文献
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{{ truncateString('JEFFREY M FIELD', 18)}}的其他基金
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- 批准号:
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$ 31.35万 - 项目类别:
Mutagenesis of p53 by reactive PAH and ROS
反应性 PAH 和 ROS 对 p53 的诱变
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$ 31.35万 - 项目类别:
Mutagenesis of p53 by reactive PAH and ROS
反应性 PAH 和 ROS 对 p53 的诱变
- 批准号:
8052754 - 财政年份:2008
- 资助金额:
$ 31.35万 - 项目类别:
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- 资助金额:
$ 31.35万 - 项目类别:
Mutagenesis of p53 by reactive PAH and ROS
反应性 PAH 和 ROS 对 p53 的诱变
- 批准号:
8235068 - 财政年份:2008
- 资助金额:
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