Hormonal Regulation of Messenger RNA Stability
信使 RNA 稳定性的激素调节
基本信息
- 批准号:7888589
- 负责人:
- 金额:$ 45.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1987
- 资助国家:美国
- 起止时间:1987-04-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsActinsAffinity ChromatographyAmino AcidsAppearanceBindingBinding ProteinsBinding SitesC-terminalCancer Cell GrowthCellsCharacteristicsCodeComplexConsensusCytoskeletonDataDevelopmentDoxycyclineElementsEnzymesEstradiolEstrogensExcisionExonucleaseFundingGatekeepingGene ExpressionGene Expression ProfileGene Expression RegulationGene ProteinsGeneric DrugsGenesGoalsGrowth FactorHalf-LifeHormonalHumanImmunofluorescence ImmunologicLinkMalignant NeoplasmsMediatingMessenger RNAModelingMolecularNatureNonsense CodonOncogenicPathway interactionsPhosphotransferasesPlayPoly APoly(A) TailPolyribosomesProcessProtein FamilyProtein Tyrosine KinaseProteinsProto-OncogenesRNA BindingRNA StabilityRNase protection assayRecoveryRecruitment ActivityResearchRibonucleasesRibosomesRoleSRC geneSerum ProteinsSignal TransductionSignaling MoleculeSpecificityStimulusTertiary Protein StructureTetanus Helper PeptideTetracyclinesTranslatingTranslationsTyrosineWorkXenopuscell motilitycytokineendonucleasehormone regulationinterestmRNA DecaymRNA Transcript Degradationmessenger ribonucleoproteinperoxidasinpolymerizationprogramsprotein-tyrosine kinase c-srcpublic health relevanceresearch studyresponsesrc Homology Region 2 Domaintranscription factorvasodilator-stimulated phosphoprotein
项目摘要
DESCRIPTION (provided by applicant): mRNA decay plays a central role in gene expression, with the half-life of virtually every mRNA controlled by regulatory sequences within the mRNA and their cognate binding proteins. Rapid turnover is a characteristic feature of mRNAs encoding growth factors, transcription factors, cytokines and cell signaling molecules, and the selective modulation of this process is one way of controlling the amount of these proteins. The decay of most mRNAs begins with shortening of the poly(A) tail, removal of the 5' cap and simultaneous 5'-3' and 3'-5' degradation of the mRNA body. With the exception of poly(A) shortening these processes act on nontranslat- ing mRNAs. However, the turnover of a subset of the transcriptome is catalyzed by endonuclease cleavage while mRNAs are engaged by translating ribosomes. The prototypical mRNA endonuclease is PMR1, an en- zyme that was originally identified as an estrogen-induced ribonuclease activity whose appearance on polysomes coincides with the destabilization of serum protein mRNAs. The hallmark of endonuclease- mediated mRNA decay is its selectivity for specific mRNAs. This is determined by the formation of an mRNP complex (termed Complex I) containing PMR1 and its translating substrate mRNA. To join this complex PMR1 must be phosphorylated on a tyrosine residue in the polysome-targeting domain of the protein, and the past funding cycle identified c-Src as the kinase that is responsible for this key activation step. This is the first example of direct involvement of an oncogenic tyrosine kinase in mRNA decay, and it raises the possibility that PMR1-mediated mRNA decay may be a target of c-Src in cancer. Consistent with this, PMR1 binds to the Ena/VASP proteins, which are regulators of the actin cytoskeleton, and cell motility is increased in cells ex- pressing catalytically-active PMR1. Aim 1 will use tandem affinity chromatography to recover the Complex I mRNP, identify its constituent proteins, and determine their role in mRNP assembly and mRNA decay. This is the first step toward deciphering the 'RNP code' for PMR1-mRNA decay. The SH2 domain containing protein that is the 'gatekeeper' for recruiting PMR1 to the mRNP will be of particular interest, since none of these has known RNA-binding activity. Aim 2 continues work begun in the last cycle using microarrays to identify PMR1 target mRNAs by their recovery with Complex I. These will be compared to mRNAs that are selectively reduced by increasing expression of PMR1 and selectively increased by its knockdown. These will also be used to identify shared sequence or structural features that together with proteins in Aim 1 define the substrate mRNP. Cell motility is increased in cells expressing active PMR1, and the experiments in Aim 3 will use imag- ing of cell movement, quantitative PCR and immunofluorescence to examine the relationship between motility, PMR1 binding to the Ena/VASP proteins, and its recruitment to Complex I. The long-term goal of this work is to understand the molecular mechanisms of PMR1-mediated mRNA decay, how it is regulated and its role in con- trolling gene expression during development, in response to hormonal stimuli, and in malignancy.
PUBLIC HEALTH RELEVANCE: mRNA decay is a key step in gene regulation. PMR1 is an mRNA endonuclease that is activated by the oncogenic tyrosine kinase c-Src to degrade a distinct subset of mRNAs. PMR1-mediated mRNA decay is also associated with increased cell motility, raising the possibility of a link between this form of mRNA decay, the c- Src protooncogene and cancer. This research seeks to identify the components of the PMR1 decay complex, identify the scope of PMR1-mediated decay and relate both of these to the invasive growth of cancer cells.
描述(由申请人提供):mRNA 衰变在基因表达中起着核心作用,几乎每个 mRNA 的半衰期都由 mRNA 及其同源结合蛋白内的调节序列控制。快速周转是编码生长因子、转录因子、细胞因子和细胞信号分子的 mRNA 的一个特征,选择性调节这一过程是控制这些蛋白质数量的一种方法。大多数 mRNA 的衰变始于 Poly(A) 尾的缩短、5' 帽的去除以及 mRNA 体同时 5'-3' 和 3'-5' 的降解。除了 Poly(A) 缩短之外,这些过程都作用于非翻译 mRNA。然而,转录组子集的周转是由核酸内切酶切割催化的,而 mRNA 是通过翻译核糖体参与的。典型的 mRNA 核酸内切酶是 PMR1,这种酶最初被鉴定为雌激素诱导的核糖核酸酶活性,其在多聚体上的出现与血清蛋白 mRNA 的不稳定相一致。核酸内切酶介导的 mRNA 降解的特点是其对特定 mRNA 的选择性。这是由含有 PMR1 及其翻译底物 mRNA 的 mRNP 复合物(称为复合物 I)的形成决定的。为了加入这个复杂的 PMR1,必须在蛋白质多核糖体靶向结构域的酪氨酸残基上进行磷酸化,过去的资助周期将 c-Src 确定为负责这一关键激活步骤的激酶。这是致癌酪氨酸激酶直接参与 mRNA 衰变的第一个例子,它提出了 PMR1 介导的 mRNA 衰变可能是癌症中 c-Src 的靶标的可能性。与此一致的是,PMR1 与 Ena/VASP 蛋白结合,后者是肌动蛋白细胞骨架的调节因子,并且表达催化活性 PMR1 的细胞的细胞运动性增加。目标 1 将使用串联亲和层析来回收复合物 I mRNP,鉴定其组成蛋白,并确定它们在 mRNP 组装和 mRNA 衰减中的作用。这是破译 PMR1-mRNA 衰变“RNP 代码”的第一步。含有 SH2 结构域的蛋白质是招募 PMR1 到 mRNP 的“看门人”,将受到特别关注,因为这些蛋白质都不具有已知的 RNA 结合活性。目标 2 继续上一个周期开始的工作,使用微阵列通过复合物 I 的恢复来识别 PMR1 靶 mRNA。这些将与通过增加 PMR1 表达选择性减少和通过其敲低选择性增加的 mRNA 进行比较。这些也将用于识别与 Aim 1 中的蛋白质一起定义底物 mRNP 的共享序列或结构特征。表达活性 PMR1 的细胞的细胞运动性增加,Aim 3 中的实验将使用细胞运动成像、定量 PCR 和免疫荧光来检查运动性、PMR1 与 Ena/VASP 蛋白的结合以及其招募到复合物 I 之间的关系。这项工作的长期目标是了解 PMR1 介导的 mRNA 衰变的分子机制、它是如何被调节的及其在反转录过程中的作用。 在发育过程中、对激素刺激的反应以及恶性肿瘤中控制基因表达。
公共卫生相关性:mRNA 衰减是基因调控的关键步骤。 PMR1 是一种 mRNA 核酸内切酶,由致癌酪氨酸激酶 c-Src 激活,可降解特定的 mRNA 子集。 PMR1 介导的 mRNA 衰减也与细胞运动性增加有关,这增加了这种形式的 mRNA 衰减、c-Src 原癌基因和癌症之间存在联系的可能性。这项研究旨在鉴定 PMR1 衰变复合物的组成部分,确定 PMR1 介导的衰变范围,并将这两者与癌细胞的侵袭性生长联系起来。
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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DANIEL R. SCHOENBERG其他文献
DANIEL R. SCHOENBERG的其他文献
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{{ truncateString('DANIEL R. SCHOENBERG', 18)}}的其他基金
Relationship of Cytoplasmic Capping to Post-transcriptional Gene Regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
7888807 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Relationship of cytoplasmic capping to post-transcriptional gene regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
9249712 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Relationship of Cytoplasmic Capping to Post-transcriptional Gene Regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
8445319 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Relationship of Cytoplasmic Capping to Post-transcriptional Gene Regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
8040924 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Relationship of cytoplasmic capping to post-transcriptional gene regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
9118224 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Relationship of Cytoplasmic Capping to Post-transcriptional Gene Regulation
细胞质加帽与转录后基因调控的关系
- 批准号:
8242018 - 财政年份:2010
- 资助金额:
$ 45.81万 - 项目类别:
Nonsense codon activation of endonuclease-mediated mRNA decay
核酸内切酶介导的 mRNA 衰变的无义密码子激活
- 批准号:
8208188 - 财政年份:2009
- 资助金额:
$ 45.81万 - 项目类别:
Nonsense codon activation of endonuclease-mediated mRNA decay
核酸内切酶介导的 mRNA 衰变的无义密码子激活
- 批准号:
7751927 - 财政年份:2009
- 资助金额:
$ 45.81万 - 项目类别:
Nonsense codon activation of endonuclease-mediated mRNA decay
核酸内切酶介导的 mRNA 衰变的无义密码子激活
- 批准号:
8004999 - 财政年份:2009
- 资助金额:
$ 45.81万 - 项目类别:
Beta-globin mRNA decay in erythroid cells
红细胞中的 β-珠蛋白 mRNA 衰减
- 批准号:
6752342 - 财政年份:2004
- 资助金额:
$ 45.81万 - 项目类别:
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