Mediator Kinases and Transcription Regulation
介导激酶和转录调控
基本信息
- 批准号:9306137
- 负责人:
- 金额:$ 39.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-28 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityArchitectureBehaviorBiologicalBiological AssayBiological ProcessCancer BiologyCell physiologyCellsCodeCollaborationsComplementComplexCrystallizationDNA BindingDNA Polymerase IDNA Polymerase IIDataDevelopmentDiseaseEnhancersEnzymesFoundationsGenesGenetic TranscriptionGoalsGrantHCT116 CellsHumanHuman DevelopmentIn VitroLeadLinkMalignant NeoplasmsMapsMass Spectrum AnalysisMediator of activation proteinMolecularMutagenesisPathway interactionsPhosphorylationPhosphotransferasesPlayPositioning AttributeProteinsPublishingRNA Polymerase IReagentRegulationResearch PersonnelRoleSerumSignal PathwaySignal TransductionSolidStructural ModelsStructureTechniquesTechnologyTestingTherapeuticTimeTranscriptTranscriptional RegulationTransfer RNAUniversitiesUntranslated RNAValidationX-Ray Crystallographybasecell growthcortistatincrosslinkexperimental studyfollow-upgenome wide association studygenome-wideglobal run on sequencinghuman diseasein vitro testingin vivoinhibitor/antagonistinnovationinsightkinase inhibitorknock-downmouse modelneuron developmentnovel therapeuticsparalogous genephosphoproteomicspublic health relevanceresponsesmall moleculetechnology validationthree-dimensional modelingtranscription factortumorigenesis
项目摘要
DESCRIPTION (provided by applicant): This collaborative project seeks to gain a deep mechanistic understanding of the Mediator kinases (CDK8 and CDK19) and the CDK8 module. CDK8 and its paralog, CDK19, are considered "Mediator kinases" because of their stable, but reversible, association with the 26-subunit Mediator complex. Mediator is a global regulator of pol II transcription and appears to be required for expression of perhaps all pol II transcripts, which include all protein-coding and most non-coding RNA genes. CDK8 and CDK19 are linked to a growing number of cancers and developmental diseases, indicative of their essential-yet poorly understood-biological roles. Here, we propose to study CDK8 and CDK19 function in the context of serum response signaling, which is fundamentally important for cell physiology, development, and cancer biology. CDK8 in particular (CDK19 is less studied) has been shown to regulate transcription of serum response genes; however, the mechanisms remain unclear due to inherent limitations with cellular knockdown approaches. Working with our collaborator Dr. Matt Shair (Harvard), we have characterized a small molecule that is an extremely potent and selective Mediator kinase (CDK8 and CDK19) inhibitor. Using this reagent, we can for the first time reliably assess the mechanistic roles of Mediator kinases in human cells. In the context
of serum response, we will identify the kinase substrates for CDK8 and CDK19 by using SILAC phosphoproteomics (with/without the Mediator kinase inhibitor). Also during serum response, we will use GRO-Seq to determine how Mediator kinases affect transcription genome-wide. GRO-Seq is uniquely suited to address these questions because, among other reasons, it provides a direct and immediate picture of active transcription (including all classes of transcripts-antisense, divergent, eRNA, lncRNA, tRNA, and so on), which is essential for understanding the rapid (within minutes) cellular response to serum stimulation. CDK8 functions in the context of a four-subunit, 600 kDa "CDK8 module" that also contains CCNC, MED12, and MED13. Because of its genome-wide association with Mediator, the CDK8 module seems poised to broadly regulate pol II transcription. The structure of the CDK8 module is poorly understood, which limits our understanding of the molecular mechanisms that regulate its essential biological functions. In Aim 2, we seek to define the 3D architecture and identify functionally relevant interfaces within the CDK8 module by applying well-tested crosslinking-mass spectrometry (CXMS) approaches and innovative 3D modeling techniques. These data will be supported by detailed in vitro mechanistic studies and cell-based functional validation assays, with a goal of defining the molecular mechanisms by which the CDK8 module regulates pol II transcription and how its kinase activity is regulated. Collectively, the diverse and complementary set of experiments proposed should yield fundamental insights regarding CDK8 module and Mediator kinase function that should drive the field in new directions.
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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{{ truncateString('Dylan J Taatjes', 18)}}的其他基金
Mechanisms of RNA polymerase II transcription regulation
RNA聚合酶II转录调控机制
- 批准号:
10321903 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Supplemental request for MAX-TL Ultracentrifuge and rotor
MAX-TL 超速离心机和转子的补充请求
- 批准号:
10386257 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Mechanisms of RNA polymerase II transcription regulation
RNA聚合酶II转录调控机制
- 批准号:
10536613 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Mediator kinases as interferon antagonists in Down Syndrome
介导激酶作为唐氏综合症干扰素拮抗剂
- 批准号:
10461951 - 财政年份:2020
- 资助金额:
$ 39.56万 - 项目类别:
Mediator kinases as interferon antagonists in Down Syndrome
介导激酶作为唐氏综合症干扰素拮抗剂
- 批准号:
10677733 - 财政年份:2020
- 资助金额:
$ 39.56万 - 项目类别:
Mediator kinases as interferon antagonists in Down Syndrome
介导激酶作为唐氏综合症干扰素拮抗剂
- 批准号:
10114912 - 财政年份:2020
- 资助金额:
$ 39.56万 - 项目类别:
Mediator kinases as interferon antagonists in Down Syndrome
介导激酶作为唐氏综合症干扰素拮抗剂
- 批准号:
10268243 - 财政年份:2020
- 资助金额:
$ 39.56万 - 项目类别:
Biochemical Analysis of a p53 Isoform that Accelerates Mammalian Aging
加速哺乳动物衰老的 p53 异构体的生化分析
- 批准号:
7773565 - 财政年份:2010
- 资助金额:
$ 39.56万 - 项目类别:
Biochemical Analysis of a p53 Isoform that Accelerates Mammalian Aging
加速哺乳动物衰老的 p53 异构体的生化分析
- 批准号:
8016662 - 财政年份:2010
- 资助金额:
$ 39.56万 - 项目类别:
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