Molecular basis of MED12 in the pathogenesis of uterine fibroids
MED12在子宫肌瘤发病机制中的分子基础
基本信息
- 批准号:10539362
- 负责人:
- 金额:$ 36.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressBenignBindingBiochemicalCellsChemicalsChromosomal BreaksChromosomal InstabilityCryoelectron MicroscopyDefectDevelopmentDrug TargetingDrug usageEnhancersEnzyme KineticsEnzymesEtiologyFibroid TumorFunctional disorderGene ExpressionGeneticGenetic TranscriptionGenetic TransformationGenomic InstabilityHabitual AbortionHealth Care CostsImpairmentInduced MutationInfertilityLeiomyomaLinkMass Spectrum AnalysisMeasuresMediator of activation proteinMedicalMenorrhagiaMitoticMolecularMolecular ConformationMonitorMorbidity - disease rateMuscleMutationMyometrialOperative Surgical ProceduresOutputPathogenesisPathogenicityPathway interactionsPelvic PainPharmaceutical PreparationsPhenotypePhosphotransferasesPolymerasePre-Clinical ModelPremature LaborRNA Polymerase IIRecurrenceRoleRouteSOX8 geneSeedsSomatic MutationStructural BiochemistryStructureTestingTherapeuticTherapeutic InterventionTranscription InitiationTranscriptional RegulationTreatment EfficacyUterine FibroidsWomen&aposs Healthatomic interactionsbiological adaptation to stresscell growthcell transformationclinically relevantcrosslinkdosagedriver mutationeffective therapyefficacy evaluationgenome-widein vivoinhibitorinsightmouse modelmutantneoplasticnovelnovel therapeuticspre-clinicalprogramspromoterreplication stresssegregationself-renewalsmall moleculestem cell differentiationstem cellsstress kinasestructural biologytranscription factortumortumor growthtumor initiationtumor progressiontumorigenic
项目摘要
PROJECT SUMMARY/ABSTRACT
Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide. As no long-
term non-invasive treatment option exists for UFs, deeper insight into tumor etiology is key to develop more
effective therapies. Accordingly, this proposal is impactful as it suggests a novel etiological basis for the
predominant UF subtype and further offers proof of concept for therapeutic intervention in this specific
genetic setting. UFs arise from the genetic transformation of a single myometrial stem cell (MM SC) into a tumor
initiating cell (UF SC) that seeds monoclonal tumor growth. Notably, recurrent somatic mutations in the RNA
polymerase II (RNAPII) Mediator subunit MED12 account for ~70% of UFs, but how these mutations drive cell
transformation and tumor formation is unclear. Previously, we showed that MED12 mutations disrupt CycC-
CDK8 kinase activity in Mediator, revealing the first and heretofore only known biochemical defect arising from
these pathogenic mutations and further implying a new etiological role for CDK8 in UF pathogenesis. This
breakthrough discovery was the basis for our original application which spawned major advances that justify
studies in this renewal application to clarify the molecular basis and therapeutic implications of Mediator kinase
dysfunction in the pathogenesis of MED12-mutant UFs. Herein, we show that MED12 mutations impair CDK8
activity through T-loop destabilization, leading to a profoundly altered phosphoproteome and dysregulation
of cell growth and myogenic gene expression programs that dictate MM SC fate. Further, we show that
MED12 mutation-induced CDK8 inactivation triggers R-loop-dependent replication stress, suggesting a
possible basis for genomic instability and a new therapeutic vulnerability in this dominant UF subclass.
Accordingly, we hypothesize that MED12 mutation-induced Mediator kinase disruption drives tumor initiation
and progression through aberrant MM SC reprogramming and replication stress-dependent chromosomal
instability. We further propose that clinically relevant ATR axis inhibitors will provide therapeutic benefit in a
preclinical model of MED12-mutant UFs. To test this, we will: (1) Elucidate the biochemical basis by which
MED12 mutations disrupt Mediator kinase activity. Using structural biology and biochemistry, we will determine
the impact of mutant MED12 on CDK8 T-loop stability and conformational dynamics as well as CycC-CDK8
substrate binding and catalytic efficiency; (2) Elucidate the molecular basis by which Mediator kinase disruption
drives UF initiation. We will link Mediator kinase-dependent changes in MM SC self-renewal and differentiation
with genome-wide enhancer reprogramming and altered transcriptional output and further ask if Mediator kinase
disruption can reprogram MM SCs to form UF tumors vivo; (3) Elucidate the molecular basis by which Mediator
kinase disruption drives UF progression. We will investigate RNAPII promoter pausing defects as a basis for
aberrant R-loop accrual, determine if R-loop-induced replication stress triggers mitotic chromosomal breaks, and
evaluate the efficacy of ATR axis inhibitors in a preclinical mouse model of MED12-mutant UFs.
项目概要/摘要
子宫肌瘤(UF)是全球女性健康最重要的良性肿瘤威胁。
UF 存在术语非侵入性治疗选择,深入了解肿瘤病因是开发更多药物的关键
因此,该提议具有影响力,因为它为该疾病提供了新的病因学基础。
主要的 UF 亚型,并进一步为这一特定的治疗干预提供了概念证明
UF 源自单个子宫肌层干细胞 (MM SC) 向肿瘤的遗传转化。
引发单克隆肿瘤生长的起始细胞(UF SC)值得注意的是,RNA 中反复发生体细胞突变。
聚合酶 II (RNAPII) 介导亚基 MED12 约占 UF 的 70%,但这些突变如何驱动细胞
此前,我们发现 MED12 突变会破坏 CycC-。
Mediator 中的 CDK8 激酶活性,揭示了第一个也是迄今为止唯一已知的生化缺陷
这些致病突变进一步暗示了 CDK8 在 UF 发病机制中的新病因学作用。
突破性的发现是我们最初应用的基础,它产生了重大进步,证明了这一点
本次更新申请中的研究旨在阐明介导激酶的分子基础和治疗意义
MED12 突变 UF 发病机制中的功能障碍在此,我们表明 MED12 突变会损害 CDK8。
通过 T 环不稳定来抑制活性,导致磷酸蛋白质组发生深刻改变和失调
细胞生长和肌源性基因表达程序决定了 MM SC 的命运。
MED12 突变诱导的 CDK8 失活触发 R 环依赖性复制应激,表明
基因组不稳定性的可能基础和这一主要 UF 亚类的新治疗脆弱性。
因此,我们研究 MED12 突变诱导的介导激酶破坏驱动肿瘤发生
以及通过异常 MM SC 重编程和复制应激依赖性染色体进展
我们进一步提出临床相关的 ATR 轴抑制剂将提供治疗益处。
MED12 突变体 UF 的临床前模型 为了测试这一点,我们将: (1) 阐明其生化基础。
MED12 突变会破坏介导激酶活性。我们将利用结构生物学和生物化学来确定。
突变体 MED12 对 CDK8 T 环稳定性和构象动力学以及 CycC-CDK8 的影响
(2) 阐明介导激酶破坏的分子基础
我们将把介导激酶依赖性变化与 MM SC 自我更新和分化联系起来。
具有全基因组增强子重编程和转录输出,并进一步询问介体激酶是否
(3) 阐明Mediator的分子基础
我们将研究 RNAPII 启动子暂停缺陷作为基础。
异常的 R 环累积,确定 R 环诱导的复制应激是否触发有丝分裂染色体断裂,以及
评估 ATR 轴抑制剂在 MED12 突变 UF 临床前小鼠模型中的功效。
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)
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THOMAS G BOYER其他文献
THOMAS G BOYER的其他文献
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{{ truncateString('THOMAS G BOYER', 18)}}的其他基金
Molecular basis of MED12 in the pathogenesis of uterine fibroids
MED12在子宫肌瘤发病机制中的分子基础
- 批准号:
10672272 - 财政年份:2017
- 资助金额:
$ 36.37万 - 项目类别:
Molecular basis of MED12 in the pathogenesis of uterine fibroids
MED12在子宫肌瘤发病机制中的分子基础
- 批准号:
9237368 - 财政年份:2017
- 资助金额:
$ 36.37万 - 项目类别:
Molecular basis of MED12 in the pathogenesis of uterine fibroids
MED12在子宫肌瘤发病机制中的分子基础
- 批准号:
9927654 - 财政年份:2017
- 资助金额:
$ 36.37万 - 项目类别:
Mediator and epigenetic control of neuronal gene expression and differentiation
神经元基因表达和分化的介质和表观遗传控制
- 批准号:
8015297 - 财政年份:2009
- 资助金额:
$ 36.37万 - 项目类别:
Mediator and epigenetic control of neuronal gene expression and differentiation
神经元基因表达和分化的介质和表观遗传控制
- 批准号:
8414862 - 财政年份:2009
- 资助金额:
$ 36.37万 - 项目类别:
Mediator and epigenetic control of neuronal gene expression and differentiation
神经元基因表达和分化的介质和表观遗传控制
- 批准号:
7590982 - 财政年份:2009
- 资助金额:
$ 36.37万 - 项目类别:
Mediator and epigenetic control of neuronal gene expression and differentiation
神经元基因表达和分化的介质和表观遗传控制
- 批准号:
7799858 - 财政年份:2009
- 资助金额:
$ 36.37万 - 项目类别:
Mediator and epigenetic control of neuronal gene expression and differentiation
神经元基因表达和分化的介质和表观遗传控制
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8213456 - 财政年份:2009
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Osteoblast differentiation: Interactions of Wnt, Runx2 and FGF
成骨细胞分化:Wnt、Runx2 和 FGF 的相互作用
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8239919 - 财政年份:2008
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$ 36.37万 - 项目类别:
Osteoblast differentiation: Interactions of Wnt, Runx2 and FGF
成骨细胞分化:Wnt、Runx2 和 FGF 的相互作用
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7798088 - 财政年份:2008
- 资助金额:
$ 36.37万 - 项目类别:
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