Mechanisms of tumor suppression by the chromatin deacetylase SIRT6
染色质脱乙酰酶 SIRT6 抑制肿瘤的机制
基本信息
- 批准号:8689985
- 负责人:
- 金额:$ 16.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AneuploidyAnimal ModelAttenuatedCancer EtiologyCarcinomaCell LineCellsChromatinChromosomal InstabilityChromosomal StabilityChromosomesCollaborationsDNADNA RepairDataDeacetylaseDefectDiseaseDissectionElementsEpigenetic ProcessEpithelial CellsEpitopesFibroblastsGene ActivationGene DeletionGenomeGenome StabilityGoalsGrowthHeterochromatinHomeostasisHumanImmunoprecipitationIntestinal NeoplasmsIntestinesLaboratoriesLarge Intestine CarcinomaLifeLinkMaintenanceMalignant - descriptorMalignant NeoplasmsMammalsMetabolicMetastatic toMissionMitoticModelingMusOncogenesOutputPathway interactionsPlayPloidiesProcessPropertyProtein FamilyProteinsPublic HealthPublishingResearchRoleSignal TransductionSirtuinsSystemTestingTumor BurdenTumor SuppressionTumor Suppressor GenesTumor Suppressor ProteinsWorkadenomaattenuationcarcinogenesiscellular imaginghypoxia inducible factor 1immortalized cellin vivoinnovationinsightlymph nodesmolecular markernoveloverexpressionprotein complexpublic health relevanceresearch studytumortumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): Loss of chromosomal stability is a common feature of human carcinomas. How cells maintain chromosomal integrity is incompletely understood; however it is clear that many pathways and protein complexes are involved. Maintenance of the correct chromosomal content (euploidy) is an important contributor to overall chromosomal stability. Emerging data indicate that epigenetic silencing of pericentromeric repetitive DNA elements plays a key role in maintenance of euploidy. Defective pericentromeric silencing is sufficient to induce chromosomal instability and, in animal models, malignancy. This application focuses on novel functions for the sirtuin SIRT6 in tumor suppression, pericentromeric silencing, and ploidy maintenance. The sirtuins are a family of protein deacetylases that promote many aspects of healthspan in mammals, among them tumor suppression. The long- term goal of the laboratory is to elucidate mechanisms by which sirtuins, in particular SIRT6, promote healthspan. Recently published work by the applicant's laboratory has shown that SIRT6 functions as an intestinal tumor suppressor in humans and mice, at least in part via attenuation of MYC and HIF1 signaling. The objective of this application is to elucidate a third role of SIRT6 in tumor suppression, specifically in pericentromeric silencing and chromosomal stability. The central hypothesis of this application is that SIRT6 promotes epigenetic silencing of pericentromeric DNA to promote euploidy maintenance, a function that contributes to its tumor suppressor function. The rationale for these studies is that a mechanistic dissection of the relationships between SIRT6, pericentromeric silencing, and euploidy will contribute to an enhanced understanding of chromosomal stability overall. This work will be carried out in three Specific Aims. First, the significance of SIRT6's interactions with known chromatin silencing factors will be elucidated. Potential mitotic defects in SIRT6-deficient cells will be identified b live-cell imaging. Second, the impact of loss of SIRT6 function will be assessed in intestinal epithelial cells and adenomas with respect to malignant properties and induction of aneuploidy. Third, the ability of SIRT6 overexpression to suppress adenomatosis will be tested in vivo. The approach is innovative, in that the contribution of pericentromeric silencing to ploidy maintenance is still incompletely understood, and SIRT6 has not previously been linked to this process. The work is significant, in that it is likely to provide new insights into mechanisms of ploidy maintenance, which in turn is a major factor in overall genomic stability and tumor suppression.
描述(由申请人提供):染色体稳定性丧失是人类癌症的一个共同特征。细胞如何维持染色体完整性尚不完全清楚;然而,很明显涉及许多途径和蛋白质复合物。维持正确的染色体内容(整倍性)是染色体整体稳定性的重要贡献者。新数据表明,着丝粒周围重复 DNA 元件的表观遗传沉默在整倍性的维持中发挥着关键作用。有缺陷的着丝粒周围沉默足以诱发染色体不稳定,并且在动物模型中诱发恶性肿瘤。本申请重点关注 Sirtuin SIRT6 在肿瘤抑制、着丝粒周围沉默和倍性维持方面的新功能。 Sirtuins 是一个蛋白质脱乙酰酶家族,可促进哺乳动物健康寿命的许多方面,其中包括肿瘤抑制。该实验室的长期目标是阐明去乙酰化酶(特别是 SIRT6)促进健康寿命的机制。申请人实验室最近发表的工作表明,SIRT6 在人类和小鼠中发挥肠道肿瘤抑制因子的作用,至少部分是通过减弱 MYC 和 HIF1 信号传导来发挥作用。本申请的目的是阐明 SIRT6 在肿瘤抑制中的第三个作用,特别是在着丝粒周围沉默和染色体稳定性方面。该应用的中心假设是 SIRT6 促进着丝粒周围 DNA 的表观遗传沉默,以促进整倍性维持,这一功能有助于其肿瘤抑制功能。这些研究的基本原理是,对 SIRT6、着丝粒周围沉默和整倍性之间关系的机械剖析将有助于增强对染色体整体稳定性的理解。这项工作将围绕三个具体目标进行。首先,将阐明 SIRT6 与已知染色质沉默因子相互作用的重要性。 SIRT6 缺陷细胞中潜在的有丝分裂缺陷将通过活细胞成像来识别。其次,将评估肠上皮细胞和腺瘤中 SIRT6 功能丧失对恶性特性和非整倍性诱导的影响。第三,将在体内测试SIRT6过表达抑制腺瘤病的能力。该方法具有创新性,因为着丝粒周围沉默对倍性维持的贡献仍不完全清楚,并且 SIRT6 以前从未与此过程相关联。这项工作意义重大,因为它可能为倍性维持机制提供新的见解,而倍性维持机制又是整体基因组稳定性和肿瘤抑制的主要因素。
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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David Benner Lombard其他文献
David Benner Lombard的其他文献
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Mechanisms of age-associated cardiac heterochromatin dysfunction
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Mechanisms of tumor suppression by the chromatin deacetylase SIRT6
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- 批准号:
8564971 - 财政年份:2013
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8826143 - 财政年份:2012
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Mechanisms of tumor suppression by the chromatin deacetylase SIRT6
染色质脱乙酰酶 SIRT6 抑制肿瘤的机制
- 批准号:
8564971 - 财政年份:2013
- 资助金额:
$ 16.17万 - 项目类别: