Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
基本信息
- 批准号:10306386
- 负责人:
- 金额:$ 36.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsBase Excision RepairsBindingBiochemical ProcessBiological AssayCDKN2A geneCDT1 GeneCarcinogensCell CycleCellsChromiumCountryDNADNA AdductsDNA DamageDNA Double Strand BreakDNA RepairDataDoseEnvironmental ExposureEnvironmental PollutionEnvironmental Risk FactorExcisionExposure toFemaleG1 ArrestG1 PhaseGene ExpressionGeneticGenetic SuppressionGenetic TranscriptionGenotoxic StressGlutathioneHealthHumanIndividualIndustrializationIngestionKnowledgeLaboratory AnimalsLicensing FactorLung NeoplasmsMDM2 geneMaintenanceMalignant NeoplasmsMetabolismMetalsMismatch RepairModelingMusMutationNational Toxicology ProgramNon-linear ModelsNucleotide Excision RepairOccupational ExposureOccupationsProteinsPublic HealthRegulationReplication InitiationReplication LicensingRiskRisk AssessmentRodentRoleSignal TransductionSmall IntestinesSourceSpecificitySquamous Cell Lung CarcinomaStressTP53 geneTestingTissuesTobacco smokeTransactivationUp-RegulationWaterWorkWorkplaceadductanimal dataascorbatebiological adaptation to stresscancer cellcancer riskcancer typecarcinogenicitycell transformationchromium hexavalent ioncytotoxicitydrinking waterepidemiology studygenome integritygenotoxicityimprovedin vivoinhibitormalenovelpreservationpromoterrespiratoryresponsesuperfund sitetoxic metaltranscription factor
项目摘要
Project Summary
Hexavalent chromium [Cr(VI)] is firmly established as a human carcinogen by epidemiological studies
in occupationally exposed groups from different countries. The presence of this toxic metal at
numerous Superfund sites and in drinking water across many states has also raised significant public
health concerns regarding cancer and other health risks associated with environmental exposures to
Cr(VI). Ingestion of Cr(VI) through drinking water produced clear evidence of carcinogenicity in the
small intestine of mice. The low-dose extrapolation of these animal data to environmental risks in
humans requires knowledge of the mechanism of the carcinogenic action for Cr(VI), which dictates
the use of specific extrapolation models. Cr(VI) generates Cr-DNA adducts as the most abundant
form of DNA damage but these adducts are weakly duplex-distorting and do not induce classic DNA
damage responses. This project will investigate a hypothesis on a major role of DNA repair products
of the initially formed Cr-DNA damage in the activation of noncanonical branches of genotoxic stress
signaling. We will also examine the biochemical processes governing the responsiveness of the
stress-sensitive transcription factor p53 and a protective G1 checkpoint to Cr-DNA damage. The
completion of this work is expected to provide mechanistic explanations for unusual genetic features
of Cr(VI)-induced lung tumors and improve human risk assessment.
项目摘要
流行病学研究已确定六价铬[Cr(VI)]为人类致癌物
在不同国家的职业暴露人群中。这种有毒金属的存在
许多超级基金网站和许多州的饮用水也引起了公众的极大关注。
关于癌症和其他与环境接触有关的健康风险的健康问题,
Cr(VI)。通过饮用水摄入Cr(VI),
小鼠小肠。将这些动物数据低剂量外推至环境风险,
人类需要了解Cr(VI)的致癌作用机制,这表明
使用特定的外推模型。Cr(VI)生成的Cr-DNA加合物最丰富
DNA损伤的形式,但这些加合物是弱的DNA扭曲,不诱导经典的DNA
损害反应。该项目将调查关于DNA修复产物的主要作用的假设
最初形成的Cr-DNA损伤在基因毒性应激的非典型分支的激活中
发信号。我们还将研究控制反应的生化过程,
应激敏感转录因子p53和Cr-DNA损伤的保护性G1检查点。的
这项工作的完成有望为不寻常的遗传特征提供机械解释
铬(VI)诱导的肺肿瘤和改善人类风险评估。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
NAD+ metabolism controls growth inhibition by HIF1 in normoxia and determines differential sensitivity of normal and cancer cells.
NAD 代谢控制常氧条件下 HIF1 的生长抑制,并决定正常细胞和癌细胞的不同敏感性。
- DOI:10.1080/15384101.2021.1959988
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Luczak,MichalW;Krawic,Casey;Zhitkovich,Anatoly
- 通讯作者:Zhitkovich,Anatoly
Ascorbate: antioxidant and biochemical activities and their importance for in vitro models.
- DOI:10.1007/s00204-021-03167-0
- 发表时间:2021-12
- 期刊:
- 影响因子:6.1
- 作者:Zhitkovich A
- 通讯作者:Zhitkovich A
Atypical genotoxicity of carcinogenic nickel(II): Linkage to dNTP biosynthesis, DNA-incorporated rNMPs, and impaired repair of TOP1-DNA crosslinks.
- DOI:10.1016/j.jbc.2023.105385
- 发表时间:2023-12
- 期刊:
- 影响因子:4.8
- 作者:Krawic, Casey;Luczak, Michal W.;Valiente, Sophia;Zhitkovich, Anatoly
- 通讯作者:Zhitkovich, Anatoly
Chemical mechanisms of DNA damage by carcinogenic chromium(VI).
致癌性六价铬对 DNA 损伤的化学机制。
- DOI:10.1016/bs.apha.2022.07.003
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Krawic,Casey;Zhitkovich,Anatoly
- 通讯作者:Zhitkovich,Anatoly
Heat Shock Proteins and HSF1 in Cancer.
- DOI:10.3389/fonc.2022.860320
- 发表时间:2022
- 期刊:
- 影响因子:4.7
- 作者:Cyran AM;Zhitkovich A
- 通讯作者:Zhitkovich A
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Anatoly Zhitkovich其他文献
Anatoly Zhitkovich的其他文献
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{{ truncateString('Anatoly Zhitkovich', 18)}}的其他基金
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10527323 - 财政年份:2020
- 资助金额:
$ 36.56万 - 项目类别:
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10304906 - 财政年份:2020
- 资助金额:
$ 36.56万 - 项目类别:
Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
- 批准号:
10057383 - 财政年份:2017
- 资助金额:
$ 36.56万 - 项目类别: