Identifying molecular mechanisms that suppress centriole amplification.
识别抑制中心粒扩增的分子机制。
基本信息
- 批准号:9055722
- 负责人:
- 金额:$ 28.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-01 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:AneuploidyBindingBiochemicalBiological AssayBiological ModelsCell CycleCell Cycle ProgressionCell Cycle RegulationCell divisionCellsCentriolesCentrosomeChromosomal InstabilityChromosome SegregationChromosomesCiliaComplementComplexCongenital AbnormalityCoupledDNA biosynthesisDataDaughterDefectDiseaseDrosophila genusElementsEnsureEtiologyEventFutureGenomeGoalsGrowthHealthIn VitroInheritedIslandKnowledgeLaboratoriesLicensingLinkLocationMediatingMeiosisMicrocephalyMicrotubulesMissionMitosisMitoticModificationMolecularMothersNormal CellOncogenicOrganellesPLK1 genePathway interactionsPatternPhosphorylationPopulationProcessProductionProteinsPublic HealthRegulationRegulatory PathwayResearchResistanceRoleS PhaseScaffolding ProteinSeckel syndromeSeriesSiteSpontaneous abortionSpottingsSurfaceSystemTestingUbiquitinWorkanaphase-promoting complexcancer cellciliopathydaughter celldriving forcein vivoinsightmutantnoveloverexpressionpreventprogramsprotein degradationresearch studystem cell divisiontumorigenesisubiquitin ligase
项目摘要
DESCRIPTION (provided by applicant): Centrioles are the duplicating elements of centrosomes, organelles which nucleate microtubule growth to build mitotic/meiotic spindles and cilia. During each normal cell division, centrioles duplicate once and once only. Like DNA replication, centriole duplication is a semi-conservative process tightly coupled to the cell cycle
and occurs only during S-phase. Centriole number must be closely regulated because a deficiency or an excess of centrioles may interfere with correct chromosome segregation and asymmetric stem cell division. The presence of too few centrioles contributes to various ciliopathies, including microcephaly, and Seckel syndrome. In contrast, too many centrioles directly promotes chromosomal instability (CIN) a driving force for aneuploidy that induces miscarriage, birth defects, and tumorigenesis. Furthermore, the presence of too many centrioles is frequently observed in cancer cells. Normally, each `mother' centriole assembles only a single `daughter', but centrioles have the capacity to assemble multiple daughters simultaneously - an aneuploidy- generating condition called centriole amplification. Normally, only a single, restricte site on the mother centriole is used to spawn a daughter. However, the mechanism limiting assembly to only this site is unknown. Experiments in this proposal test a hypothesis that explains why centriole duplication is normally restricted to a single event per mother centriole. Specifically, we link three conserved centriolar proteins, Polo-like kinase 4 (Plk4), its binding-partner and scaffolding protein Asterless (Asl), and the centriole assembly protein Anastral Spindle 2 (Ana2) into a single regulatory pathway. Overexpression of any of these proteins induces assembly of multiple daughter centrioles. How the cell cycle control program regulates these key proteins to limit daughter centriole assembly to only a single event is unknown. Here, we hypothesize that cell cycle regulators, including the Anaphase Promoting Complex (APC) ubiquitin-ligase, control the destruction of a Plk4/Asl/Ana2 complex to alter their pattern/activit on mother centrioles and generate a single site for daughter assembly. Our preliminary data indicate that 1) the Plk4 pattern on centrioles changes during mitotic progression: first coating the entire mother centriole but then being pruned to a single asymmetric spot by mitotic exit; 2) Plk4 and Ana2 are APC targets; 3) phosphorylation protects subpopulations of these proteins from degradation; and 4) Asl is a Plk4 substrate that stabilizes mitotic Plk4. In this proposal, we
will (1) determine if APC regulation of Plk4 localization on centrioles defines the site of daughte centriole assembly, (2) determine the functional interaction between Plk4 and Asl which assists in defining a single site of centriole assembly, and (3) determine if Ana2 regulates Plk4 activation and whether Ana2 is controlled by APC. These studies will provide mechanistic insight into a molecular process that governs the fidelity of centriole duplication. Understanding the process at the molecular level will guide future studies to explore the etiology of centriole amplification during tumorigenesis and other centriole-related diseases.
描述(申请人提供):中心粒是中心体的复制元素,中心体是使微管生长成核以形成有丝分裂/减数分裂纺锤体和纤毛的细胞器。在每个正常的细胞分裂过程中,中心粒只复制一次。与dna复制一样,中心粒复制是一个与细胞周期紧密相连的半保守过程。
且仅发生在S期。中心粒数量必须受到严格的控制,因为中心粒的不足或过剩可能会干扰正确的染色体分离和不对称的干细胞分裂。中心粒太少会导致各种纤毛疾病,包括小头畸形和塞克尔综合征。相反,过多的中心粒直接促进染色体不稳定(CIN),CIN是导致流产、出生缺陷和肿瘤形成的非整倍体的驱动力。此外,在癌细胞中经常可以观察到过多的中心粒。正常情况下,每个母中心粒只组装一个女儿,但中心粒有能力同时组装多个女儿--这是一种称为中心粒放大的非整倍体产生条件。正常情况下,母中心粒上只有一个受限制的位置被用来生下女儿。然而,将组装限制在这个部位的机制尚不清楚。这项提议中的实验测试了一个假说,该假说解释了为什么中心粒复制通常被限制在每个母中心粒只有一个事件。具体地说,我们将三个保守的中心粒蛋白,Polo-like kinase4(Plk4),它的结合伙伴和支架蛋白Asterless(As1),以及中心粒组装蛋白Anstar Spindle 2(Ana2)连接到一个单一的调控通路中。这些蛋白中的任何一种的过度表达都会诱导多个子代中心粒的组装。细胞周期控制程序如何调节这些关键蛋白,将子代中心粒的组装限制为只有一个事件,这一点尚不清楚。在这里,我们假设细胞周期调节因子,包括后期促进复合体(APC)泛素连接酶,控制Plk4/As1/Ana2复合体的破坏,改变它们在母中心粒上的模式/激活,并产生单个位点用于子代组装。我们的初步数据表明:1)中心粒上的Plk4模式在有丝分裂过程中发生变化:首先覆盖整个母中心粒,但随后被有丝分裂出口修剪到单个不对称的点;2)Plk4和Ana2是APC靶标;3)磷酸化保护这些蛋白质的亚群不被降解;4)As1是稳定有丝分裂Plk4的Plk4底物。在这项提案中,我们
将(1)确定APC对Plk4在中心粒上定位的调节是否定义了女儿中心粒组装的位置,(2)确定Plk4和As1之间的功能相互作用有助于确定单个中心粒组装位置,(3)确定Ana2是否调节Plk4的激活以及Ana2是否受APC控制。这些研究将为控制中心粒复制的保真度的分子过程提供机械论的见解。在分子水平上了解这一过程将指导未来的研究,以探索肿瘤发生和其他中心粒相关疾病中中心粒放大的病因。
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 }}
Gregory Charles Rogers其他文献
Gregory Charles Rogers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('Gregory Charles Rogers', 18)}}的其他基金
Characterizing the molecular mechanisms of centriole duplication, growth and maturation
表征中心粒复制、生长和成熟的分子机制
- 批准号:
10640273 - 财政年份:2020
- 资助金额:
$ 28.5万 - 项目类别:
Characterizing the molecular mechanisms of centriole duplication, growth and maturation
表征中心粒复制、生长和成熟的分子机制
- 批准号:
10166887 - 财政年份:2020
- 资助金额:
$ 28.5万 - 项目类别:
Characterizing the molecular mechanisms of centriole duplication, growth and maturation
表征中心粒复制、生长和成熟的分子机制
- 批准号:
10405016 - 财政年份:2020
- 资助金额:
$ 28.5万 - 项目类别:
Identifying molecular mechanisms that suppress centriole amplification.
识别抑制中心粒扩增的分子机制。
- 批准号:
8884942 - 财政年份:2015
- 资助金额:
$ 28.5万 - 项目类别:
Identifying molecular mechanisms that suppress centriole amplification.
识别抑制中心粒扩增的分子机制。
- 批准号:
9267488 - 财政年份:2015
- 资助金额:
$ 28.5万 - 项目类别:
相似国自然基金
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:32170319
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
- 批准号:31672538
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
番茄EIN3-binding F-box蛋白2超表达诱导单性结实和果实成熟异常的机制研究
- 批准号:31372080
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
P53 binding protein 1 调控乳腺癌进展转移及化疗敏感性的机制研究
- 批准号:81172529
- 批准年份:2011
- 资助金额:58.0 万元
- 项目类别:面上项目
DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
- 批准号:81070952
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
研究EB1(End-Binding protein 1)的癌基因特性及作用机制
- 批准号:30672361
- 批准年份:2006
- 资助金额:24.0 万元
- 项目类别:面上项目
相似海外基金
Biochemical characterization of an inflammation related protein, mTOC (Celastramycin binding protein)
炎症相关蛋白 mTOC(西拉霉素结合蛋白)的生化特征
- 批准号:
17K07346 - 财政年份:2017
- 资助金额:
$ 28.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Characterization of the impact of Arginine Methylation of RNA Binding Proteins on Their Biochemical
RNA 结合蛋白精氨酸甲基化对其生化影响的表征
- 批准号:
511321-2017 - 财政年份:2017
- 资助金额:
$ 28.5万 - 项目类别:
University Undergraduate Student Research Awards
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9335978 - 财政年份:2016
- 资助金额:
$ 28.5万 - 项目类别:
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9158657 - 财政年份:2016
- 资助金额:
$ 28.5万 - 项目类别:
EAGER: Biochemical Mechanism of Oomycete RXLR Effector Binding to PI3P
EAGER:卵菌 RXLR 效应子与 PI3P 结合的生化机制
- 批准号:
1449122 - 财政年份:2014
- 资助金额:
$ 28.5万 - 项目类别:
Standard Grant
Biochemical analysis of plant calcium-binding proteins
植物钙结合蛋白的生化分析
- 批准号:
448832-2013 - 财政年份:2013
- 资助金额:
$ 28.5万 - 项目类别:
University Undergraduate Student Research Awards
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2013
- 资助金额:
$ 28.5万 - 项目类别:
Postgraduate Scholarships - Doctoral
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2012
- 资助金额:
$ 28.5万 - 项目类别:
Postgraduate Scholarships - Doctoral
Biochemical, cellular and molecular studies to dissect the contribution of the soluble host carbohydrate binding proteins to HIV-1 pathogenesis
生化、细胞和分子研究,剖析可溶性宿主碳水化合物结合蛋白对 HIV-1 发病机制的贡献
- 批准号:
239201 - 财政年份:2011
- 资助金额:
$ 28.5万 - 项目类别:
Operating Grants
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2011
- 资助金额:
$ 28.5万 - 项目类别:
Postgraduate Scholarships - Doctoral