The Role of Peroxiredoxin1 & Reactive Oxygen Species in Breast Tumor Initiation
过氧化还原蛋白1的作用
基本信息
- 批准号:8625187
- 负责人:
- 金额:$ 29.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-07 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AgarAgingAllelesAntioxidantsApoptosisBindingBioluminescenceBreastBreast Epithelial CellsCancer EtiologyCatalytic DomainCell ProliferationCell TransplantsCellsComplexCysteineDevelopmentEnvironmental CarcinogensExhibitsFamilyFatty acid glycerol estersFibroblastsFutureGrowth FactorHRAS geneHemolytic AnemiaHumanHydrogen PeroxideIn VitroIncidenceInduction of ApoptosisInvestigationIonizing radiationLipidsMalignant NeoplasmsMammary NeoplasmsMediatingMembraneMembrane PotentialsMouse Mammary Tumor VirusMusMutationNuclearNuclear Localization SignalNude MicePTEN genePTEN proteinPeptide Signal SequencesPeptidesPeroxidasesPhosphatidylinositolsPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayPredispositionPreventiveProcessProtein DephosphorylationPumaReactive Oxygen SpeciesRegulationRoleSignal PathwaySignal TransductionTestingTobacco smokingTumor BurdenTumor SuppressionTumor Suppressor ProteinsWorkbasecell transformationcell typein vivoinsightmalignant breast neoplasmmitochondrial membranemouse modelnoveloxidationpreventpublic health relevanceradiation carcinogentooltripolyphosphatetumortumor initiationtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): It is widely accepted that reactive oxygen species (ROS), such as H2O2 promote tumorigenesis. Consequently, there is a crucial need for a greater understanding of the mechanism of H2O2-mediated cancer development. We have shown that mice lacking one or two copies of the peroxidase Prdx1 die prematurely of hemolytic anemia and multiple cancers. Furthermore, cells and mice lacking Prdx1 show a higher incidence of transformation to H-RasV12 and ErbB-2 and H-RasV12-induced breast cancer. Fibroblasts and mammary epithelial cells lacking Prdx1 show higher phosphorylation of Akt on Ser473 and more inactive (oxidized) forms of the tumor suppressor PTEN. PTEN is readily inactivated via oxidation of the low pKa cysteine in its catalytic site. We found that Prdx1 binding to PTEN is essential to protect it from oxidation-induced inactivation. The Prdx1:PTEN complex is disrupted by H2O2, upon which Akt including its downstream signaling is activated resulting in a decrease in apoptosis. Therefore, our working hypothesis is that H2O2 inactivates PTEN lipid phosphatase activity due to a complex disruption of Prdx1:PTEN, thereby promoting Akt kinase-driven oncogenesis. We further hypothesize that Prdx1:PTEN binding is required for normal PTEN function, including its lipid phosphatase activity, nuclear stability and apoptosis induction. Specific Aim1 will determine the mechanisms by which H2O2 regulates the Prdx1:PTEN interaction to alter PTEN lipid phosphatase activity and Prdx1 peroxidase activity. We will define if H2O2-induced oxidation of either Prdx1 or PTEN disrupts or prevents the Prdx1:PTEN interaction and modulates PTEN lipid phosphatase activity and Prdx1 peroxidase activity. Specific Aim2 will examine if the Prdx1:PTEN interaction promotes tumor suppression by regulating PTEN or Akt dependent mechanisms. To complete this we will examine PTEN-induced tumor suppressive functions including apoptosis upon disrupting the Prdx1:PTEN interactions by using peptide interference in vitro and in vivo. Specific Aim3 will evaluate if nuclear Prdx1 promotes tumor suppression ErbB-2-induced breast cancer in mice. We have found that loss of Prdx1 decreases nuclear PTEN protein levels. We will therefore introduce Prdx1 fused to nuclear localization signal sequence into mammary epithelial cells isolated from Prdx1-/-MMTV-ErbB-2 mice and transplant cells into clear fad pads of NCR nude mice, to observe if nuclear Prdx1 decreases incidence of breast cancer or tumor burden. Mice lacking Prdx1 offer the first mouse model where loss of a peroxidase results in elevation of endogenous H2O2 thereby causing cancer. This mouse model mimics conditions where H2O2 levels are elevated as found in aging, tobacco smoking, ionizing radiation and environmental carcinogens. By studying breast cancer prone mice lacking Prdx1 we should help to find more specific preventive treatments in H2O2-induced breast cancer.
描述(由申请人提供):人们普遍接受活性氧物种(ROS),如过氧化氢,促进肿瘤的发生。因此,迫切需要更好地了解过氧化氢介导的癌症发生的机制。我们已经证明,缺乏一到两个过氧化物酶Prdx1拷贝的小鼠会过早死于溶血性贫血和多种癌症。此外,缺乏Prdx1的细胞和小鼠对H-RasV12、ErbB-2和H-RasV12诱导的乳腺癌的转化发生率更高。缺乏Prdx1的成纤维细胞和乳腺上皮细胞表现出更高的Akt在Ser473上的磷酸化,以及更多不活跃(氧化)的肿瘤抑制因子PTEN。PTEN很容易通过其催化部位低pKA半胱氨酸的氧化而失活。我们发现Prdx1与PTEN的结合对于保护其免受氧化诱导的失活是必不可少的。Prdx1:PTEN复合体被H_2O_2破坏,Akt及其下游信号被激活,导致细胞凋亡减少。因此,我们的工作假设是,由于Prdx1:PTEN的复杂干扰,过氧化氢使PTEN脂磷酸酶活性失活,从而促进Akt激酶驱动的肿瘤发生。我们进一步假设,Prdx1:PTEN结合是正常PTEN功能所必需的,包括其脂质磷酸酶活性、核稳定性和诱导细胞凋亡。特异的Aim1将决定过氧化氢调节Prdx1:PTEN相互作用以改变PTEN脂磷酸酶活性和Prdx1过氧化物酶活性的机制。我们将确定过氧化氢诱导的Prdx1或PTEN的氧化是否破坏或阻止Prdx1:PTEN的相互作用,并调节PTEN脂磷酸酶活性和Prdx1过氧化物酶活性。特异性AIM2将检测Prdx1:PTEN相互作用是否通过调节PTEN或Akt依赖机制促进肿瘤抑制。为了完成这项工作,我们将在体外和体内通过多肽干扰来检测PTEN诱导的肿瘤抑制功能,包括在破坏Prdx1:PTEN相互作用时的细胞凋亡。特异性Aim3将评估核Prdx1是否促进ErbB-2诱导的小鼠乳腺癌的抑制。我们发现Prdx1的缺失降低了核PTEN蛋白的水平。因此,我们将融合了核定位信号序列的Prdx1导入从Prdx1-/-MMTV-ErbB-2小鼠乳腺上皮细胞中分离出来,并将其移植到NCR裸鼠的透明FAD垫中,观察核Prdx1是否能降低乳腺癌的发病率或肿瘤负担。缺乏Prdx1的小鼠提供了第一个过氧化物酶丢失导致内源性过氧化氢升高从而导致癌症的小鼠模型。这个小鼠模型模拟了在衰老、吸烟、电离辐射和环境致癌物中发现的过氧化氢水平升高的情况。通过研究缺乏Prdx1的乳腺癌易感小鼠,我们应该有助于在过氧化氢诱导的乳腺癌中找到更具体的预防治疗方法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mimicking Embedded Vasculature Structure for 3D Cancer on a Chip Approaches through Micromilling.
- DOI:10.1038/s41598-017-16458-3
- 发表时间:2017-12-01
- 期刊:
- 影响因子:4.6
- 作者:Wan L;Skoko J;Yu J;Ozdoganlar OB;LeDuc PR;Neumann CA
- 通讯作者:Neumann CA
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CAROLA ANKE NEUMANN其他文献
CAROLA ANKE NEUMANN的其他文献
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{{ truncateString('CAROLA ANKE NEUMANN', 18)}}的其他基金
Synergize a novel homologous recombination inhibitor with DNA damagingagents in TNBC
在 TNBC 中协同新型同源重组抑制剂与 DNA 损伤剂
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10760604 - 财政年份:2023
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$ 29.94万 - 项目类别:
Inhibition of DNA double strand break repair in TNBC by nitro-fatty acids
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9816235 - 财政年份:2019
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$ 29.94万 - 项目类别:
Inhibition of DNA double strand break repair in TNBC by nitro-fatty acids
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10002190 - 财政年份:2019
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Identifying underlying mechanisms of intracellular changes in response to caregiv
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- 批准号:
8539752 - 财政年份:2012
- 资助金额:
$ 29.94万 - 项目类别:
The Role of Peroxiredoxin1 & Reactive Oxygen Species in Breast Tumor Initiation
过氧化还原蛋白1的作用
- 批准号:
8433458 - 财政年份:2010
- 资助金额:
$ 29.94万 - 项目类别:
The Role of Peroxiredoxin1 & Reactive Oxygen Species in Breast Tumor Initiation
过氧化还原蛋白1的作用
- 批准号:
7875086 - 财政年份:2010
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$ 29.94万 - 项目类别:
The Role of Peroxiredoxin1 & Reactive Oxygen Species in Breast Tumor Initiation
过氧化还原蛋白1的作用
- 批准号:
8220850 - 财政年份:2010
- 资助金额:
$ 29.94万 - 项目类别:
The Role of Peroxiredoxin1 & Reactive Oxygen Species in Breast Tumor Initiation
过氧化还原蛋白1的作用
- 批准号:
8056527 - 财政年份:2010
- 资助金额:
$ 29.94万 - 项目类别:
Role of Prdx 1 in Natural Killer Cells and Tumorigenesis
Prdx 1 在自然杀伤细胞和肿瘤发生中的作用
- 批准号:
6780310 - 财政年份:2005
- 资助金额:
$ 29.94万 - 项目类别:
Role of Prdx 1 in Natural Killer Cells and Tumorigenesis
Prdx 1 在自然杀伤细胞和肿瘤发生中的作用
- 批准号:
7118959 - 财政年份:2005
- 资助金额:
$ 29.94万 - 项目类别:
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