Control of protein degradation and transcriptional dynamics in the auxin response
生长素反应中蛋白质降解和转录动力学的控制
基本信息
- 批准号:9896837
- 负责人:
- 金额:$ 30.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-05-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAreaAuxinsBiochemicalBiologicalBiological AssayBiologyCell Cycle ProgressionCellsChromatinComplexCullin ProteinsDevelopmentDiabetes MellitusDiagnosisDrug TargetingEngineeringEukaryotaEventEvolutionExcisionF Box DomainF-Box ProteinsFamilyFamily memberFungal ProteinsFutureGene ExpressionGenetic TranscriptionGoalsHandHeartHomeostasisHumanHuman DevelopmentHuman GenomeIndividualKineticsLateralLinkLogicMaintenanceMalignant NeoplasmsMediatingModelingMolecularMolecular AnalysisMorphogenesisNatureNeurodegenerative DisordersOrganismPacemakersPathway interactionsPhosphorylationPlant RootsPlantsProcessPropertyProtein KinaseProteinsReporter GenesRepressionResolutionSignal PathwaySignal TransductionSpecificityStructureSubstrate InteractionSystemTechnologyTestingTherapeuticTimeTranscriptional ActivationTranscriptional RegulationTransgenic PlantsTranslatingUbiquitinVariantWorkYeastsbasecell typecircadian pacemakercomputerized toolsdesigndrug discoveryexperimental studygene repressiongenetic corepressorhuman diseaseimprovedinsightinterestmembermolecular modelingnovelorgan growthplant fungiprotein complexprotein degradationrate of changereceptorresponsesmall moleculestem cell fate specificationtherapy designtooltranscriptometranscriptomicsubiquitin-protein ligase
项目摘要
The rate of protein turnover can act as a pacemaker to coordinate responses within and between cells, and is
frequently dysregulated in human disease. Yet we know remarkably little about what controls substrate
degradation kinetics or how these kinetics translate into downstream responses. One possible reason is the
lack of available models for high- resolution structure-function analysis of degradation and transcriptional
activation. The SCF class of E3 ubiquitin ligases is highly conserved among animals, plants and fungi. We
propose to use an SCF involved in auxin response, at the heart of nearly every aspect of plant biology, as a
model to investigate general principles underlying E3 function and connect that function to transcriptional
activation and morphogenesis. The small-molecule triggered degradation in the auxin pathway offers a unique
advantage for these studies, and has facilitated our engineering of auxin-induced degradation and
transcriptional activation in yeast. Work with this system has led to our central hypothesis: the auxin system
functions as a universal developmental timer in plants, and similar logic circuits likely act in most eukaryotes.
To test this hypothesis, we propose to: (1) Define the determinants and relevance of variation in degradation
rates. We have already identified several domains of interest in E3 and substrate components, and are using
synthetic and computational tools to connect individual residues to degradation dynamics. (2) Quantify the
impact of degradation rate on transcriptional repression. We have extended our synthetic assays to include
auxin-induced transcription. We can now quantitatively track the molecular events between substrate turnover
and downstream responses over time. This technology enables our study of previously intractable problems
like how the removal of co-repressors is integrated with transcriptional activation. (3) Couple cellular
degradation timers to developmental transitions. We have shown in transgenic plants that substrate
degradation rate sets the pace of lateral organ development. We will use multiple, complementary approaches
to analyze the transcriptome of these plants to elucidate how the timing of substrate turnover regulates
developmental progression in a cell-type-dependent manner. Together, the proposed work will provide a
mechanistic framework for E3 function in the auxin response and potentially provide insights into fundamental
properties of E3:substrate interactions and downstream events. These insights can inform our understanding
of E3s associated with human disease, as well as guiding future design of synthetic circuits using auxin
components for therapeutic applications.
蛋白质周转的速度可以作为一个起搏器来协调细胞内和细胞之间的反应,并且
经常在人类疾病中失调。然而,我们对控制底物的因素知之甚少。
降解动力学或这些动力学如何转化为下游反应。一个可能的原因是
缺乏用于高分辨率结构-功能降解和转录分析的模型
激活。SCF类E3泛素连接酶在动物、植物和真菌中高度保守。我们
建议使用参与生长素反应的SCF,几乎是植物生物学各个方面的核心,作为一种
研究E3功能的一般原理并将该功能与转录相关的模型
激活和形态发生。小分子引发的生长素途径的降解提供了一个独特的
有利于这些研究,并促进了我们对生长素诱导的降解和
酵母中的转录激活。对这一系统的研究得出了我们的中心假设:生长素系统
在植物中起着普遍的发育计时器的作用,类似的逻辑电路可能在大多数真核生物中起作用。
为了验证这一假设,我们建议:(1)定义退化过程中变异的决定因素和相关性
费率。我们已经确定了E3和衬底组件中的几个感兴趣的领域,并正在使用
将单个残留物与降解动力学联系起来的合成和计算工具。(2)量化
降解率对转录抑制的影响。我们已经将我们的合成化验扩展到包括
生长素诱导转录。我们现在可以定量跟踪底物周转之间的分子事件
以及随着时间的推移而产生的下游反应。这项技术使我们能够研究以前难以解决的问题
比如协同抑制因子的去除是如何与转录激活相结合的。(3)耦合蜂窝
退化到发育转变的时间。我们已经在转基因植物中证明了底物
降解率决定了侧器官发育的速度。我们将使用多种互补的方法
分析这些植物的转录组,以阐明底物周转的时间如何调节
以一种依赖细胞类型的方式进行发育。总之,拟议的工作将提供一个
E3在生长素反应中作用的机制框架,并可能提供对基础知识的洞察
E3的性质:底物相互作用和下游事件。这些见解可以帮助我们理解
与人类疾病相关的E3,以及指导未来使用生长素的合成电路设计
用于治疗应用的组件。
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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JENNIFER L NEMHAUSER其他文献
JENNIFER L NEMHAUSER的其他文献
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{{ truncateString('JENNIFER L NEMHAUSER', 18)}}的其他基金
Control of protein degradation and transcriptional dynamics in the auxin response
生长素反应中蛋白质降解和转录动力学的控制
- 批准号:
10549582 - 财政年份:2023
- 资助金额:
$ 30.47万 - 项目类别:
Control of protein degradation dynamics in the auxin response
生长素反应中蛋白质降解动力学的控制
- 批准号:
9015773 - 财政年份:2014
- 资助金额:
$ 30.47万 - 项目类别:
Control of protein degradation and transcriptional dynamics in the auxin response
生长素反应中蛋白质降解和转录动力学的控制
- 批准号:
10356847 - 财政年份:2014
- 资助金额:
$ 30.47万 - 项目类别:
Control of protein degradation and transcriptional dynamics in the auxin response
生长素反应中蛋白质降解和转录动力学的控制
- 批准号:
10115746 - 财政年份:2014
- 资助金额:
$ 30.47万 - 项目类别:
Control of protein degradation dynamics in the auxin response
生长素反应中蛋白质降解动力学的控制
- 批准号:
8695018 - 财政年份:2014
- 资助金额:
$ 30.47万 - 项目类别:
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