Mechanism and Regulation of eIF6 in Translation
eIF6翻译机制及调控
基本信息
- 批准号:10444189
- 负责人:
- 金额:$ 31.12万
- 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:2022-07-07 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAllosteric RegulationAminoacyl-tRNA hydrolaseBindingBiochemicalBiological AssayBiological ModelsBiophysicsCell CycleCell NucleolusCell SurvivalCellsCellular AssayChildhood LeukemiaColon CarcinomaComplexDataDeuteriumDiseaseDisease ProgressionDissociationEnsureEukaryotic Initiation FactorsEventGTP BindingGenerationsGoalsGrowthGrowth and Development functionGuanosine Triphosphate PhosphohydrolasesHumanHydrogenHydrolysisImpairmentInheritedLinkMalignant NeoplasmsMass Spectrum AnalysisMediatingMessenger RNAMetabolic DiseasesMethodologyMitosisModelingMolecularMutationPathogenesisPathologicPatientsPeptide Initiation FactorsPhenotypePhosphorylationPhysiologicalProcessPrognosisProliferatingProtein BiosynthesisProtein DeregulationQuality ControlRPL10 geneRegulationRibonucleoproteinsRibosomal RNARibosomesRoleShwachman-Diamond syndromeSiteTailTestingTherapeuticTimeTissue MicroarrayTrans-ActivatorsTranslation InitiationTranslationsTumor-DerivedUp-RegulationWorkaurora B kinasebasecancer cellcancer subtypescancer typeexperimental studyin vivoinsightleukemiamalignant breast neoplasmmouse modelmutantnew therapeutic targetnoveloverexpressionrelease factorsingle moleculetherapeutic developmenttherapeutic targettriple-negative invasive breast carcinomatumorigenesis
项目摘要
PROJECT SUMMARY
Ribosomes are large ribonucleoprotein complexes that are integral to translational control. The assembly and
maturation of ribosomal subunits involves a multitude of trans-acting factors that render the subunits
translationally competent. Maturation of the 60S ribosomal subunit is accomplished by the release of eukaryotic
initiation factor-6 (eIF6) with the help of the maturation factors-SBDS and EFL1-GTPase. eIF6 sterically hinders
association of the 60S and 40S subunits and therefore, its release from 60S is critical to permit interactions
between 60S and the mRNA-bound 40S subunits. In addition, eIF6 is essential for rRNA processing in the
nucleolus and is associated with the translationally stalled 60S-ribosome quality control complex. Given its
essential roles, the spatial and temporal aspects of eIF6 activities and its release from 60S must be tightly
regulated to ensure successful initiation of translation. Impaired release of eIF6 is the defining hallmark of certain
ribosomopathies: Shwachman-Diamond syndrome and RPL10 mutations-driven pediatric leukemias. eIF6 levels
are also deregulated in several cancers and its enhanced expression is associated with a poor prognosis.
Remarkably, restricting eIF6 levels inhibits growth of certain cancers without affecting normal growth. Therefore,
targeting eIF6 and its release from 60S has been proposed to be a desirable therapeutic strategy for cancers
and ribosomopathies. However, we are yet to understand the role of eIF6 in modulating the distinct steps of 60S
assembly and maturation. Also, the molecular mechanisms that regulate eIF6 interactions with the 60S are not
completely understood. Towards understanding these mechanisms, our recent work has identified key residues
in critical interfaces of eIF6 that modulate its interaction with 60S, and our preliminary data provide direct
evidence that the disruption of this interaction is detrimental to cancer cell viability. We have also identified novel
sites of regulation in the C-terminus of eIF6 and have uncovered its importance for controlling translational rates.
Building on these discoveries, in the current proposal we aim to define the mechanistic steps that promote the
release of eIF6 by SBDS, and EFL1 from distinct functional states of 60S and to uncover the role of GTPase
activity of EFL1 using a rigorous set of biochemical, biophysical, and single molecule approaches. In addition,
we aim to uncover the mechanism of allosteric regulation by the C-terminus of eIF6 and elucidate the functional
and phenotypic effects of disease-specific mutations of eIF6 using cellular and in vivo approaches. These studies
will provide crucial mechanistic insight into 60S dynamics and will enable the development of therapeutics
focused on eIF6 and its regulators.
项目摘要
核糖体是大的核糖核蛋白复合物,是翻译控制的组成部分。大会和
核糖体亚基的成熟涉及大量反式作用因子,这些因子使亚基
专业能力。60 S核糖体亚基的成熟是通过释放真核生物的
起始因子6(eIF 6)与成熟因子SBDS和EFL 1-GT3的辅助。eIF 6空间阻碍
60 S和40 S亚基的缔合,因此,其从60 S的释放对于允许相互作用至关重要
在60 S和mRNA结合的40 S亚基之间。此外,eIF 6在细胞中对rRNA加工是必不可少的。
核仁,并与抑制停滞的60 S-核糖体质量控制复合物相关。鉴于其
重要的作用,空间和时间方面的eIF 6活动和它的释放从60 S必须紧密
以确保翻译的顺利进行。eIF 6的释放受损是某些癌症的定义性标志。
核糖体病:Shwachman-Diamond综合征和RPL 10突变驱动的儿童白血病。eIF 6水平
在几种癌症中也是失调的,其增强的表达与不良预后相关。
值得注意的是,限制eIF 6水平可以抑制某些癌症的生长,而不会影响正常生长。因此,我们认为,
靶向eIF 6及其从60 S的释放已被提出是癌症的理想治疗策略
和核糖体病。然而,我们还没有了解eIF 6在调节60 S的不同步骤中的作用。
组装和成熟。此外,调节eIF 6与60 S相互作用的分子机制不是
完全理解为了了解这些机制,我们最近的工作已经确定了关键残留物
在调节其与60 S相互作用的eIF 6的关键界面中,我们的初步数据提供了直接的
有证据表明这种相互作用的破坏对癌细胞的生存力是有害的。我们还发现了新的
在eIF 6的C-末端的调节位点,并揭示了其控制翻译速率的重要性。
在这些发现的基础上,在目前的建议中,我们的目标是定义促进
通过SBDS和EFL 1从60 S的不同功能状态释放eIF 6,并揭示GTdR的作用
EFL 1的活性,使用一套严格的生化,生物物理和单分子方法。此外,本发明还提供了一种方法,
我们的目的是揭示eIF 6 C末端的变构调节机制,并阐明其功能性调节机制。
和eIF 6的疾病特异性突变的表型效应,使用细胞和体内方法。这些研究
将为60 S动力学提供关键的机制见解,并将使治疗方法的发展成为可能
专注于eIF 6及其监管机构。
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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Sofia Origanti其他文献
Sofia Origanti的其他文献
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