Cyclin C-CDK8/19 kinases in development and in cancer
发育和癌症中的细胞周期蛋白 C-CDK8/19 激酶
基本信息
- 批准号:10579308
- 负责人:
- 金额:$ 51.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAffectAlanineAllograftingAlpha Interleukin 2 ReceptorAmino AcidsAnimalsAntitumor ResponseBindingBiochemicalCD8-Positive T-LymphocytesCD8B1 geneCLN1 geneCLN2 geneCLN3 geneCancer ModelCancer PatientCatalytic DomainCell Culture TechniquesCell LineageCellsClinicalClinical TrialsCombined Modality TherapyComplementary DNAComplexCultured CellsCyclin-Dependent KinasesCyclinsCytotoxic T-LymphocytesDevelopmentEndothelial CellsEnterobacteria phage P1 Cre recombinaseGatekeepingGenetic TranscriptionGrowthHalf-LifeHumanIL2RA geneIL2RB geneImmuneImmune responseImmune systemImmunocompromised HostIn VitroInterleukin 2 ReceptorInterleukin-2Interleukin-4Knockout MiceLaboratoriesLinkLoxP-flanked alleleLymphoid CellMalignant NeoplasmsMapsMediatingMediatorMemoryModalityMolecularMusMutationNKTR geneOncogenesOutcomePatientsPeripheralPhosphorylationPhosphotransferasesPlayPolyubiquitinationProtein Complex SubunitProteinsRNA Polymerase IIRegulatory T-LymphocyteResearchRoleSaccharomyces cerevisiaeSignal TransductionSiteT cell differentiationT-Cell DevelopmentT-LymphocyteT-Lymphocyte SubsetsTestingThymus GlandTranscriptTumor ImmunityTumor PromotionUp-RegulationWild Type MouseWorkXenograft procedureYeastsZNF145 geneadaptive immune responseadaptive immunityanti-CTLA4 antibodiesanti-PD-1anti-canceranti-tumor immune responseantitumor effectcancer cellcancer therapycyclin Ccyclin G1effector T cellexperimental studygenetic approachimmune checkpoint blockadein vivoinhibitormouse geneticsnoveloverexpressionparalogous geneperipheral lymphoid organsmall moleculesmall molecule inhibitorsystemic toxicitytherapeutic targetthymocytetranscription factortumortumorigenesisubiquitin-protein ligase
项目摘要
Project Summary/Abstract
Cyclin C was cloned, along with other G1 cyclins, as a cDNA which can rescue the proliferative block in yeast
Saccharomyces cerevisiae lacking CLN1, CLN2 and CLN3 genes. Subsequent work revealed that cyclin C,
acting together with its kinase partners, the cyclin-dependent kinase 8 (CDK8) and CDK19, plays a role in
regulating gene transcription. Cyclin C serves as a regulatory partner of CDK8 and CDK19, and activates the
kinase activity of these proteins. The two paralog kinases show substantial overall amino acid identity,
particularly within their catalytic domains. Cyclin C, CDK8 and CDK19 represent parts of the mediator
complex, a large multisubunit protein complex that regulates gene transcription by linking RNA polymerase II to
sequence-specific transcription factors. In addition, cyclin C-CDK8/19 was shown to phosphorylate various
transcription factors and to regulate their stability and activity. Growing evidence indicates that cyclin C-CDK8
and C-CDK19 kinases may represent potential anti-cancer targets. CDK8 has been identified as an oncogene
in several human cancers. Cyclin C, CDK8 and CDK19 are overexpressed in a wide range of tumor types.
Importantly, higher expression of these three proteins was found to be associated with poor clinical outcome.
Consistent with tumor-promoting roles for cyclin C-CDK8/19, treatment of mice bearing xenografts of several
human tumor types with small molecule CDK8/19 inhibitors resulted in a potent anti-tumor effect without
apparent systemic toxicity. To understand the molecular function of cyclin C in vivo, we generated conditional
cyclin C knockout mice (cyclin CF/F). To test the impact of cyclin C-CDK8/19 inhibition on T cell development
and adaptive anti-tumor immunity, we crossed cyclin CF/F mice with CD4-Cre animals. The latter strain
expresses Cre recombinase at an early stage of T cell development, and drives deletion of the ‘floxed’
sequences in all T cell subsets. In our preliminary analyses we established that cyclin C functions as a gate-
keeper of T cell differentiation, likely by directly phosphorylating a lineage-specific transcription factor. By
doing so, cyclin C affects signaling networks that regulate the immune response. Hence, this novel function of
cyclin C may have a profound effect on the anti-tumor immune response and on tumorigenesis. In the
proposed work we will extend these studies. In Aim 1, we will study the exact molecular function of cyclin C-
CDK8 and C-CDK19 in the T cell lineage using a combination of biochemical in vitro studies, cell culture
experiments, analyses of ex vivo cultured T cells as well as mouse genetic approaches. In Aim 2, we will study
how ablation of cyclin C impacts tumorigenesis in vivo, using mouse cancer models and combination
treatments with other anti-cancer modalities. In Aim 3, we will extend these cancer studies to cyclin C catalytic
partners, using conditional Cdk19 knockout mice (Cdk19F/F), that my laboratory generated for this purpose.
The expected overall impact of this proposal is that it will reveal a novel and important function of cyclin C-
CDK8 and C-CDK19 in tumorigenesis, and will validate these kinases as attractive therapeutic targets.
项目总结/摘要
细胞周期蛋白C与其他G1期细胞周期蛋白沿着被克隆,作为一种可以拯救酵母增殖阻滞的cDNA
缺乏CLN 1、CLN 2和CLN 3基因的酿酒酵母。随后的研究表明,细胞周期蛋白C,
与其激酶伴侣细胞周期蛋白依赖性激酶8(CDK 8)和CDK 19一起作用,在
调节基因转录。细胞周期蛋白C作为CDK 8和CDK 19的调节伙伴,并激活细胞周期蛋白C。
这些蛋白质的激酶活性。这两种帕金森病激酶显示出基本的总体氨基酸同一性,
特别是在它们的催化域内。细胞周期蛋白C、CDK 8和CDK 19代表介导因子的一部分
复合物,一种大的多亚基蛋白复合物,通过连接RNA聚合酶II与
序列特异性转录因子。此外,细胞周期蛋白C-CDK 8/19被证明磷酸化各种细胞周期蛋白。
转录因子,并调节其稳定性和活性。越来越多的证据表明细胞周期蛋白C-CDK 8
C-CDK 19激酶可能是潜在的抗癌靶点。CDK 8已被鉴定为癌基因
在几种人类癌症中。细胞周期蛋白C、CDK 8和CDK 19在广泛的肿瘤类型中过表达。
重要的是,发现这三种蛋白质的较高表达与较差的临床结果相关。
与细胞周期蛋白C-CDK 8/19的肿瘤促进作用一致,对携带几种细胞周期蛋白C-CDK 8/19的异种移植物的小鼠进行治疗,
使用小分子CDK 8/19抑制剂的人肿瘤类型导致有效的抗肿瘤作用,
明显的全身毒性。为了了解细胞周期蛋白C在体内的分子功能,我们产生了条件性的
细胞周期蛋白C敲除小鼠(细胞周期蛋白CF/F)。测试细胞周期蛋白C-CDK 8/19抑制对T细胞发育的影响
和适应性抗肿瘤免疫,我们将cyclin CF/F小鼠与CD 4-Cre动物杂交。后一种菌株
在T细胞发育的早期阶段表达Cre重组酶,并驱动"floxed“
所有T细胞亚群中的序列。在我们的初步分析中,我们确定了细胞周期蛋白C的功能是一个门-
T细胞分化的保持者,可能通过直接磷酸化谱系特异性转录因子。通过
这样,细胞周期蛋白C就影响调节免疫反应的信号网络。因此,
细胞周期蛋白C可能对抗肿瘤免疫应答和肿瘤发生具有深远的影响。在
我们会继续进行这些研究。在目的1中,我们将研究细胞周期蛋白C的确切分子功能,
CDK 8和C-CDK 19在T细胞谱系中使用生物化学体外研究、细胞培养
实验,离体培养的T细胞的分析以及小鼠遗传方法。在目标2中,我们将研究
使用小鼠癌症模型和组合,
与其他抗癌方式的治疗。在目标3中,我们将这些癌症研究扩展到细胞周期蛋白C催化
合作伙伴,使用条件性Cdk 19敲除小鼠(Cdk 19 F/F),我的实验室为此目的产生。
这项提议的预期总体影响是,它将揭示细胞周期蛋白C的一个新的和重要的功能,
CDK 8和C-CDK 19在肿瘤发生中的作用,并将验证这些激酶作为有吸引力的治疗靶点。
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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Peter Sicinski其他文献
Peter Sicinski的其他文献
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{{ truncateString('Peter Sicinski', 18)}}的其他基金
Cyclin C-CDK8/19 kinases in development and in cancer
发育和癌症中的细胞周期蛋白 C-CDK8/19 激酶
- 批准号:
10415467 - 财政年份:2022
- 资助金额:
$ 51.55万 - 项目类别:
Targeting CDK4 and CDK6 kinases in breast cancer development
靶向乳腺癌发展中的 CDK4 和 CDK6 激酶
- 批准号:
10627976 - 财政年份:2020
- 资助金额:
$ 51.55万 - 项目类别:
Targeting CDK4 and CDK6 kinases in breast cancer development
靶向乳腺癌发展中的 CDK4 和 CDK6 激酶
- 批准号:
10434105 - 财政年份:2020
- 资助金额:
$ 51.55万 - 项目类别:
Targeting CDK4 and CDK6 kinases in breast cancer development
靶向乳腺癌发展中的 CDK4 和 CDK6 激酶
- 批准号:
10261468 - 财政年份:2020
- 资助金额:
$ 51.55万 - 项目类别:
Targeting CDK4 and CDK6 kinases in breast cancer development
靶向乳腺癌发展中的 CDK4 和 CDK6 激酶
- 批准号:
10023399 - 财政年份:2020
- 资助金额:
$ 51.55万 - 项目类别:
CDC7 kinase in normal and cancer cells: potential implications for cancer treatment
正常细胞和癌细胞中的 CDC7 激酶:对癌症治疗的潜在影响
- 批准号:
10063864 - 财政年份:2019
- 资助金额:
$ 51.55万 - 项目类别:
CDC7 kinase in normal and cancer cells: potential implications for cancer treatment
正常细胞和癌细胞中的 CDC7 激酶:对癌症治疗的潜在影响
- 批准号:
10526420 - 财政年份:2019
- 资助金额:
$ 51.55万 - 项目类别:
CDC7 kinase in normal and cancer cells: potential implications for cancer treatment
正常细胞和癌细胞中的 CDC7 激酶:对癌症治疗的潜在影响
- 批准号:
9916522 - 财政年份:2019
- 资助金额:
$ 51.55万 - 项目类别:
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