Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
基本信息
- 批准号:10370800
- 负责人:
- 金额:$ 0.73万
- 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:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsCell CycleCell Cycle ArrestCell Cycle RegulationCell divisionCellsChemicalsColon CarcinomaComplexCouplingCyclin-Dependent KinasesDependenceDiseaseDrug CombinationsDrug TargetingElongation FactorEnsureEnzymesEventFailureFission YeastGene ExpressionGene Expression RegulationGeneticGenetic TranscriptionGoalsHumanHuman DevelopmentKineticsLeadLinkMalignant NeoplasmsModelingPathway interactionsPharmaceutical PreparationsPhasePhosphorylationPolyadenylationPolymerasePositive Transcriptional Elongation Factor BProtein phosphataseProteinsRNA Polymerase IIRNA ProcessingRegulationSignal TransductionSpecificitySpeedTP53 geneTestingTherapeutic AgentsTimeTranscription ElongationTranscriptional RegulationYeastsanalogcancer cellchemical geneticscyclin T1cyclin-dependent kinase-activating kinasedrug discoveryfunctional genomicsgenetic approachinhibitor/antagonistmutantnovelpromoter
项目摘要
Project Summary
Cyclin-dependent kinases (CDKs) regulate cell division and transcription. To understand the mechanisms of
this regulation, or to target the CDK network in cancer cells, we need to identify the functions and substrates of
specific CDKs. To achieve this goal, we pioneered a chemical-genetic approach combining the specificity of
genetics with the speed and reversibility of chemical inhibition, by replacement of wild-type with analog-
sensitive (AS) mutant CDKs in living cells. In the next five years, we will combine chemical genetics with
functional genomics in novel ways, to establish new paradigms of cell-cycle and transcriptional control, and to
discover new pathways that interact with the CDK network, which might be targeted in cancer.
The CAK-CDK network in cell-cycle control: Our studies revealed distinct activation pathways for CDKs that
act in different phases of the cell cycle; a goal for the next five years is to understand how those pathways are
regulated by upstream signaling and linked to cell cycle-regulated transcription. We will investigate how a
cascade comprising the CDK-activating kinase (CAK) Cdk7 and its target Cdk4 is switched on in G1 when
quiescent cells re-enter the division cycle, and how Cdk7 is specifically down-regulated as cells exit the cycle.
CDK regulation of the transcription cycle: Inhibiting transcriptional CDKs perturbs RNA polymerase (Pol) II
dynamics in ways reminiscent of cell-cycle arrests and checkpoint failures, but the precise mechanisms still
need to be defined. Cdk7 is required to establish a promoter-proximal pause in the transition from initiation to
elongation, and to promote pause release by activating positive transcription elongation factor b (P-TEFb, a
Cdk9/cyclin T1 complex). We showed that normal Pol II elongation rates depend on Cdk9 activity in fission
yeast, and defined sets of human and yeast Cdk9 substrates, which are enriched for proteins implicated in
RNA processing. Over the next five years, we will test the idea that Cdk9 acts on different substrates to
stimulate both transcription elongation and RNA processing, to ensure their kinetic coupling.
Defining a transcription exit network: CDK regulation persists to the end of the transcription cycle; we
validated the termination enzyme Xrn2 and protein phosphatase 1 (PP1, implicated in cleavage and
polyadenylation) as bona fide Cdk9 substrates. Phosphorylation by Cdk9 activates Xrn2 but inhibits PP1,
which is required to dephosphorylate the elongation factor (and Cdk9 target) Spt5. In the next five years we will
test the emergent model of a bistable Cdk9-PP1 switch that controls the elongation-termination transition.
Chemical-genetic discovery of synthetic-lethal interactions CDKs have emerged as targets of drugs that
exploit transcriptional dependencies unique to certain cancer cells. We induced such a dependency in colon
cancer cells by combining activators of the tumor suppressor p53 with inhibitors of Cdk7 to achieve synthetic
lethality. In the next five years, we will uncover novel pathways that interact with the CDK network—and might
lead to anti-cancer drug combinations—by synthetic-lethal screens in human cells dependent on AS CDKs.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROBERT P FISHER其他文献
ROBERT P FISHER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ROBERT P FISHER', 18)}}的其他基金
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
10559139 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
10378005 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
Cyclin-dependent kinase control of cell-division and transcription cycles
细胞分裂和转录周期的细胞周期蛋白依赖性激酶控制
- 批准号:
9903405 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
- 批准号:
8630081 - 财政年份:2014
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
- 批准号:
8806563 - 财政年份:2014
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetics of Transcriptional Regulation by CDKs in Human Cells
人类细胞中 CDK 转录调控的化学遗传学
- 批准号:
9198169 - 财政年份:2014
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8727082 - 财政年份:2013
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
9128664 - 财政年份:2013
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8479753 - 财政年份:2013
- 资助金额:
$ 0.73万 - 项目类别:
Chemical Genetic Analysis of the Human Cell Cycle
人类细胞周期的化学遗传分析
- 批准号:
8919920 - 财政年份:2013
- 资助金额:
$ 0.73万 - 项目类别:
相似海外基金
DND1 Mediates Epigenetic Reprogramming During Cell Cycle Arrest In Male Germ Cells
DND1 在雄性生殖细胞细胞周期停滞期间介导表观遗传重编程
- 批准号:
10642896 - 财政年份:2021
- 资助金额:
$ 0.73万 - 项目类别:
DND1 Mediates Epigenetic Reprogramming During Cell Cycle Arrest In Male Germ Cells
DND1 在雄性生殖细胞细胞周期停滞期间介导表观遗传重编程
- 批准号:
10490349 - 财政年份:2021
- 资助金额:
$ 0.73万 - 项目类别:
DND1 Mediates Epigenetic Reprogramming During Cell Cycle Arrest In Male Germ Cells
DND1 在雄性生殖细胞细胞周期停滞期间介导表观遗传重编程
- 批准号:
10382834 - 财政年份:2021
- 资助金额:
$ 0.73万 - 项目类别:
Roles of Nrf2 on postanatal oxigen-rich environment-induced cardiomyocyte cell cycle arrest
Nrf2在产后富氧环境诱导的心肌细胞周期阻滞中的作用
- 批准号:
20K22751 - 财政年份:2020
- 资助金额:
$ 0.73万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Molecular mechanism controlling cell cycle arrest in response to stress in plant
植物响应应激而控制细胞周期停滞的分子机制
- 批准号:
19K06708 - 财政年份:2019
- 资助金额:
$ 0.73万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of the Snail1-Twist-p21 axis on cell cycle arrest and renal fibrosis development
Snail1-Twist-p21 轴在细胞周期停滞和肾纤维化发展中的作用
- 批准号:
10062964 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
How does ERK1/2 signalling drive both cell proliferation and cell cycle arrest?
ERK1/2 信号如何驱动细胞增殖和细胞周期停滞?
- 批准号:
2493293 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
Studentship
Coupling between cell cycle arrest and epithelial-to-mesenchymal transition in renal fibrosis development
肾纤维化发展中细胞周期停滞与上皮间质转化之间的耦合
- 批准号:
10923257 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
Role of the Snail1-Twist-p21 axis on cell cycle arrest and renal fibrosis development
Snail1-Twist-p21 轴在细胞周期停滞和肾纤维化发展中的作用
- 批准号:
10300999 - 财政年份:2018
- 资助金额:
$ 0.73万 - 项目类别:
A Transient Up-regulation of Retinoic Acid Signaling Induces Cell Cycle Arrest in Neonatal Mammalian Heart
视黄酸信号传导的瞬时上调诱导新生哺乳动物心脏细胞周期停滞
- 批准号:
17K09573 - 财政年份:2017
- 资助金额:
$ 0.73万 - 项目类别:
Grant-in-Aid for Scientific Research (C)