c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
基本信息
- 批准号:7915972
- 负责人:
- 金额:$ 6.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelApoptosisBinding SitesCancer cell lineCell Cycle RegulationCell DeathCell ProliferationCell physiologyCellsDataFamily memberFeedbackGene ExpressionGene TargetingGenesGoalsHomeostasisHumanIn VitroLightLymphomaLymphomagenesisMalignant NeoplasmsMediatingMethodologyMethodsMicroRNAsModelingMolecularMolecular ProfilingMonitorMutateNeoplastic Cell TransformationNucleotidesOncogenesOncogenicPathologicPhenotypePhysiologicalProto-OncogenesPublishingRNARegulationRepressionResearch DesignResearch PersonnelRoleSeriesSignal TransductionSiteStagingTestingTherapeutic InterventionTranscriptTumor Suppressor Proteinsc-myc Genescancer cellcell transformationcell typechromatin immunoprecipitationcohortdesigngene repressionin vivo Modelmemberneoplasticnoveloverexpressionprogramsprotein functionresearch studytherapeutic developmenttranscription factortumortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Dysregulated expression of the c-MYC proto-oncogene is one of the most frequent abnormalities in human malignancies. Through the control of an expansive target gene network, this transcription factor drives proliferation and, in some settings, induces cell death. Despite great advances in the identification of c-Myc-regulated genes, the mechanisms through which this oncogene promotes tumorigenesis are not yet fully understood. MicroRNAs are ~18-24 nucleotide RNA molecules that have emerged as major regulators of eukaryotic gene expression. We recently identified a group of microRNAs, known as the mir-17 cluster, that are directly upregulated by c-Myc. Independently, these microRNAs were shown to cooperate with c-Myc in promoting tumorigenesis. We have now also identified a cohort of microRNAs that are directly repressed by c-Myc. Many of these are known to be deleted or mutated in cancer, suggesting that they possess tumor suppressor activity. We now propose studies designed to test the hypothesis that these c-Myc-regulated microRNAs are critical components of the c-Myc target gene network that regulate cellular proliferation, apoptosis, and neoplastic transformation. In Aim 1 of this project, we will investigate the phenotypic consequences of expression or inhibition of the mir-17 cluster in multiple cell types. These experiments are necessary to set the stage for detailed molecular analyses of the mechanisms through which these microRNAs influence oncogenic phenotypes. We will begin to investigate these mechanisms in the latter part of this aim, where the hypothesis that the mir-17 cluster influences cell-cycle control through regulation of p21WAF1 is tested. In Aim 2, we will continue to dissect the mechanisms through which the mir-17 cluster influences cellular phenotypes. Here, we will test the hypothesis that the mir-17 cluster participates in a physiologic negative-feedback circuit that maintains tightly-controlled expression of c-Myc and other Myc family members in non-transformed cells. Finally, in Aim 3, we will investigate the role of microRNA repression in c-Myc-mediated tumorigenesis. MicroRNAs that are directly repressed by c-Myc will be characterized and the consequences of enforced expression of these microRNAs in in vitro and in vivo models of lymphoma will determined. We envision that these experiments will reveal novel regulatory circuitry that functions abnormally in cancer and may ultimately be amenable to therapeutic intervention.
描述(由申请方提供):c-MYC原癌基因表达失调是人类恶性肿瘤中最常见的异常之一。通过控制广泛的靶基因网络,这种转录因子驱动增殖,并在某些情况下诱导细胞死亡。尽管在鉴定c-Myc调控基因方面取得了很大进展,但这种癌基因促进肿瘤发生的机制尚未完全了解。MicroRNA是一种约18-24个核苷酸的RNA分子,已成为真核基因表达的主要调控因子。我们最近发现了一组被称为mir-17簇的microRNA,它们直接被c-Myc上调。独立地,这些微小RNA被证明与c-Myc合作促进肿瘤发生。我们现在还鉴定了一组直接被c-Myc抑制的microRNA。其中许多已知在癌症中缺失或突变,表明它们具有肿瘤抑制活性。我们现在提出的研究旨在验证这一假设,即这些c-Myc调控的microRNA是c-Myc靶基因网络的关键组成部分,调节细胞增殖,凋亡和肿瘤转化。在本项目的目标1中,我们将研究在多种细胞类型中表达或抑制mir-17簇的表型后果。这些实验是必要的,以设置详细的分子分析的机制,通过这些microRNA影响致癌表型的阶段。我们将开始调查这些机制在这一目标的后半部分,其中的假设,即mir-17簇影响细胞周期控制通过调节p21 WAF 1进行测试。在目标2中,我们将继续剖析mir-17簇影响细胞表型的机制。在这里,我们将测试的假设,即在mir-17集群参与生理负反馈电路,保持严格控制的表达c-Myc和其他Myc家族成员在非转化细胞。最后,在目标3中,我们将研究microRNA抑制在c-Myc介导的肿瘤发生中的作用。将表征直接被c-Myc抑制的microRNA,并确定这些microRNA在淋巴瘤的体外和体内模型中的强制表达的后果。我们设想,这些实验将揭示新的调节电路,在癌症中异常发挥作用,并可能最终适用于治疗干预。
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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Joshua T Mendell其他文献
Tumors line up for a letdown
肿瘤排队等待失望。
- DOI:
10.1038/ng0709-768 - 发表时间:
2009-07-01 - 期刊:
- 影响因子:29.000
- 作者:
Joshua T Mendell - 通讯作者:
Joshua T Mendell
Joshua T Mendell的其他文献
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{{ truncateString('Joshua T Mendell', 18)}}的其他基金
The role of long noncoding RNA CRNDE in normal physiology and cancer
长链非编码RNA CRNDE在正常生理和癌症中的作用
- 批准号:
10715065 - 财政年份:2023
- 资助金额:
$ 6.57万 - 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
- 批准号:
8953055 - 财政年份:2015
- 资助金额:
$ 6.57万 - 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
- 批准号:
10213661 - 财政年份:2015
- 资助金额:
$ 6.57万 - 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
- 批准号:
9125799 - 财政年份:2015
- 资助金额:
$ 6.57万 - 项目类别:
Functional Evaluation of microRNAs in Pancreatic Neoplasia
microRNA 在胰腺肿瘤中的功能评估
- 批准号:
8464662 - 财政年份:2013
- 资助金额:
$ 6.57万 - 项目类别:
Functional Evaluation of microRNAs in Pancreatic Neoplasia
microRNA 在胰腺肿瘤中的功能评估
- 批准号:
7651550 - 财政年份:2009
- 资助金额:
$ 6.57万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8026614 - 财政年份:2007
- 资助金额:
$ 6.57万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8712397 - 财政年份:2007
- 资助金额:
$ 6.57万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
8578048 - 财政年份:2007
- 资助金额:
$ 6.57万 - 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
- 批准号:
7766253 - 财政年份:2007
- 资助金额:
$ 6.57万 - 项目类别:
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