Mitochondrial and nuclear functions of NKX3.1 in regulating oxidative stress in prostate cancer
NKX3.1在调节前列腺癌氧化应激中的线粒体和核功能
基本信息
- 批准号:10058251
- 负责人:
- 金额:$ 38.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:8p21BiologicalCancerousCell NucleusCell physiologyCellsClinicalClinical ResearchComplementDNA DamageDataEarly DiagnosisEpithelialEquilibriumEventEvolutionGatekeepingGene ExpressionGenesGenetic TranscriptionGenetically Engineered MouseHomeobox GenesHomeodomain ProteinsHumanHuman ChromosomesImpairmentInflammationInterventionInvestigationKnowledgeLeadLinkLoss of HeterozygosityMaintenanceMalignant NeoplasmsMalignant neoplasm of prostateMapsMediatingMitochondriaModelingMolecularNKX3-1 geneNuclearOxidative RegulationOxidative StressPhysiologicalProcessPrognosisProstateProstatic EpitheliumProstatic Intraepithelial NeoplasiasPublishingReactive Oxygen SpeciesRegulationResearchRoleStressTissuesTranscription Regulatory ProteinWorkassaultbasecancer initiationcancer preventioncancer therapycell growth regulationefficacy testingimprovedinhibitor/antagonistloss of functionnovelpreclinical studyprostate cancer modelresponsestem cellstranscription factortumor progression
项目摘要
Project Summary/Abstract
We have been studying the processes associated with prostate differentiation and their relationship to
prostate cancer through our investigations of the NKX3.1 homeobox gene, which is a master regulator of
prostate epithelial specification that protects the prostatic epithelium from assaults associated with cancer
initiation, including oxidative stress. Our investigations have now revealed that NKX3.1 defends prostate cells
from oxidative stress by regulating gene expression in both the nucleus and mitochondria. We find that, in
addition to its expected functions as a transcriptional factor in the nucleus, NKX3.1 also localizes to
mitochondria in response to oxidative stress, where it regulates the expression of mitochondrial-encoded
genes that control reactive oxygen species (ROS). Thus, we hypothesize that NKX3.1 regulates oxidative
stress via its coordinated functions in nuclei and mitochondria, and that these functions are necessary to
maintain prostate epithelial differentiation and suppress cancer initiation. Since relatively few nuclear
transcriptional regulatory proteins have been shown to function in mitochondria, our studies provide a unique
opportunity to understand how a tissue-specific transcription factor can control oxidative stress in different sub-
cellular compartments, and the relevance of these activities for cancer.
In Aim 1, we will investigate the functions of NKX3.1 in the nucleus for protection from oxidative stress
and promotion of differentiation. We will investigate: (i) nuclear transcriptional regulatory functions of NKX3.1
for protection against oxidative stress; (ii) their relevance for prostate epithelial differentiation and cancer; and
(iii) whether and if so how these functions impact mitochondrial function. In Aim 2, we will investigate novel
functions of NKX3.1 in mitochondria. Based on our preliminary data showing that, in response to oxidative
stress, NKX3.1 becomes localized to mitochondria where it regulates the expression of mitochondrial-encoded
genes, we will investigate: (i) the mechanisms associated with localization of NKX3.1 to mitochondria; (ii) the
mechanisms by which NKX3.1 regulates mitochondrial-encoded genes, particularly in comparison with its
regulation of nuclear genes; and (iii) the importance of these mitochondrial-specific functions of NKX3.1 for
regulation of oxidative stress and cellular differentiation. In Aim 3, we will complement these mechanistic
studies by performing co-clinical studies to evaluate the relevance of regulation of oxidative stress by NKX3.1
for suppression of prostate cancer, and whether these activities can be targeted for cancer prevention using
genetically-engineered mouse models and a human prostate tissue organotypic model.
Relevance for PAR-17-203: Our proposed studies provide a unique opportunity to elucidate molecular
mechanisms that govern the balance between oxidative stress and differentiation and cancer initiation and how
these are coordinated between the nucleus and mitochondria.
项目总结/文摘
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)
专利数量(0)
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Cory Abate-Shen其他文献
Cory Abate-Shen的其他文献
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{{ truncateString('Cory Abate-Shen', 18)}}的其他基金
Investigating mechanisms of bladder cancer metastasis
研究膀胱癌转移的机制
- 批准号:
10718278 - 财政年份:2023
- 资助金额:
$ 38.71万 - 项目类别:
Project 2: Investigating cell intrinsic and extrinsic drivers of prostate cancer bone metastasis
项目2:研究前列腺癌骨转移的细胞内在和外在驱动因素
- 批准号:
10333944 - 财政年份:2022
- 资助金额:
$ 38.71万 - 项目类别:
Project 2: Investigating cell intrinsic and extrinsic drivers of prostate cancer bone metastasis
项目2:研究前列腺癌骨转移的细胞内在和外在驱动因素
- 批准号:
10612353 - 财政年份:2022
- 资助金额:
$ 38.71万 - 项目类别:
Modeling bladder cancer pathogenesis and tumor evolution
膀胱癌发病机制和肿瘤进化建模
- 批准号:
10475011 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Mitochondrial and nuclear functions of NKX3.1 in regulating oxidative stress in prostate cancer
NKX3.1在调节前列腺癌氧化应激中的线粒体和核功能
- 批准号:
10308021 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Modeling bladder cancer pathogenesis and tumor evolution
膀胱癌发病机制和肿瘤进化建模
- 批准号:
10218075 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Project 2: Functions of ARID1A in muscle invasive bladder cancer
项目2:ARID1A在肌层浸润性膀胱癌中的功能
- 批准号:
10475016 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Project 2: Functions of ARID1A in muscle invasive bladder cancer
项目2:ARID1A在肌层浸润性膀胱癌中的功能
- 批准号:
10218078 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
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