ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
基本信息
- 批准号:10586587
- 负责人:
- 金额:$ 38.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-10 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AddressBiochemicalCancer EtiologyCell CycleChromatinChromatin Remodeling FactorComplexConflict (Psychology)DNA RepairDrosophila genusDrosophila melanogasterEpigenetic ProcessEukaryotaFrequenciesFunctional disorderGenesGeneticGenomeGenomicsGoalsHistonesHumanHuman GenomeIn VitroKnowledgeMalignant - descriptorMalignant NeoplasmsMass Spectrum AnalysisMeasurementMeasuresMethodsModificationMolecularMutateMutationNeurodevelopmental DisorderNormal CellNucleosomesOncogenicPRC1 ProteinPathogenesisPhenotypePlayPolycombPost-Translational Protein ProcessingRepressionRoleShapesSiteSpecificitySquamous Cell Lung CarcinomaSquamous cell carcinomaTechniquesTestingTherapeuticTherapeutic InterventionTumor Suppressor ProteinsYeastscancer cellchromatin remodelingcrosslinkdefined contributiondosageflyhistone modificationin vivoloss of function mutationmammalian genomenon-geneticnovel therapeutic interventionrate of changesynovial sarcomatherapeutic developmenttherapeutically effective
项目摘要
Project Summary
ATP-Dependent Chromatin Remodeling in Cancer
Chromatin and epigenetic regulators have emerged as important contributors to human cancer. The subunits
of the mSWI/SNF or BAF ATP-dependent chromatin remodeling complex are mutated in over 20% of human
cancers. In addition, several other ATP-dependent remodelers make important contributions to the
pathogenesis of specific cancers. These complexes often function as genetically dominant tumor suppressors,
however the BAF complex also plays oncogenic roles in synovial sarcoma and squamous cell carcinoma.
Despite their prevalent roles in human cancer their oncogenic mechanism(s) remain unclear and a detailed
molecular understanding, necessary for therapeutic development, has been elusive. One of the most well
documented roles of BAF complexes is their opposition to Polycomb Repressive Complexes (PRC)
complexes. Indeed, BAF subunits were discovered in flies as suppressors of PRC1 mutations. In addition,
inhibition of PRC is therapeutic in some cancers having loss of function mutations in the BAF complex.
However, the mechanisms underlying the opposition between BAF chromatin remodeling complexes and
Polycomb complexes is still unclear. We will obtain a detailed understanding of the physical interaction
between these complexes and explore their oncogenic roles with the goal of identifying potential sites of
therapeutic intervention. One possible mechanism underlying the BAF-PRC opposition is the potential of BAF
complexes to exchange or evict nucleosomes modified by PRC1 and 2. Measured rates of nucleosome
exchange by several techniques and by several groups show that nucleosomes exchange several times per
cell cycle. This observation seems inconsistent with the widely held concept that histone and/or nucleosome
modifications are the basis of epigenetic and phenotypic stability. Another way of stating this is “why do the 32
SNF2-like ATP-dependent remodelers encoded in the mammalian genome not quickly erase all histone
modifications by nucleosome exchange? This conflict would be resolved if nucleosome exchange by ATP-
dependent remodelers was selective to a specific remodeler and a specific nucleosomal modification. Thus,
we are developing two new techniques that will fill this gap in our knowledge by measuring exchange of
specifically modified nucleosomes and attributing them to specific remodelers, including their post translational
or oncogenic modifications. These techniques should allow the understanding of the paradox that rates of
nucleosome exchange appear to be far faster than the rate of change of histone modifications. We will use
these techniques to assign changes in the epigenetic landscape to specific ATP-dependent chromatin
regulators and to understand the stability of epigenetic histone modifications in normal and malignant cells. At
the conclusion of our studies, we hope to have a deeper and more detailed understanding of both the normal
and oncogenic mechanisms related to mutation or dysfunction of the mSWI/SNF or BAF chromatin remodeling
complex.
项目概要
癌症中 ATP 依赖性染色质重塑
染色质和表观遗传调节因子已成为人类癌症的重要贡献者。亚单位
超过 20% 的人类的 mSWI/SNF 或 BAF ATP 依赖性染色质重塑复合物发生突变
癌症。此外,其他几个 ATP 依赖性重塑者对
特定癌症的发病机制。这些复合物通常起到遗传显性肿瘤抑制因子的作用,
然而,BAF 复合物还在滑膜肉瘤和鳞状细胞癌中发挥致癌作用。
尽管它们在人类癌症中发挥着普遍作用,但它们的致癌机制仍不清楚,详细的研究还不清楚。
治疗发展所必需的分子理解一直难以捉摸。最好的之一
BAF 复合体的记录作用是它们与 Polycomb 抑制复合体 (PRC) 的对立
复合物。事实上,在果蝇中发现了 BAF 亚基作为 PRC1 突变的抑制因子。此外,
PRC的抑制对于一些BAF复合体中具有功能丧失突变的癌症具有治疗作用。
然而,BAF 染色质重塑复合物和 BAF 染色质重塑复合物之间的对抗机制
多梳复合物仍不清楚。我们将对物理交互有详细的了解
这些复合物之间的关系并探索它们的致癌作用,目的是确定潜在的位点
治疗干预。 BAF-PRC 反对背后的一种可能机制是 BAF 的潜力
复合物交换或驱逐 PRC1 和 2 修饰的核小体。测量的核小体速率
通过多种技术和多个组进行的交换表明,核小体每次交换多次
细胞周期。这一观察结果似乎与广泛持有的概念不一致,即组蛋白和/或核小体
修饰是表观遗传和表型稳定性的基础。另一种表述方式是“为什么 32
哺乳动物基因组中编码的 SNF2 样 ATP 依赖性重塑因子不会快速消除所有组蛋白
核小体交换修饰?如果核小体通过 ATP 交换,这个冲突就会得到解决。
依赖性重塑剂对特定重塑剂和特定核小体修饰具有选择性。因此,
我们正在开发两种新技术,通过测量交换来填补我们的知识空白
专门修饰的核小体并将它们归因于特定的重塑者,包括它们的翻译后
或致癌修饰。这些技术应该可以帮助理解以下悖论:
核小体交换似乎远远快于组蛋白修饰的变化速率。我们将使用
这些技术将表观遗传景观的变化分配给特定的 ATP 依赖性染色质
调节剂并了解正常和恶性细胞中表观遗传组蛋白修饰的稳定性。在
通过我们的研究结论,我们希望对这两种正常现象有更深入、更详细的了解。
与 mSWI/SNF 或 BAF 染色质重塑突变或功能障碍相关的致癌机制
复杂的。
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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Gerald R. Crabtree其他文献
Signaling through calcium, calcineurin, and NF-AT in lymphocyte activation and development.
在淋巴细胞激活和发育过程中通过钙、钙调神经磷酸酶和 NF-AT 发出信号。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
K. Stankunas;Isabella A. Graef;J. Neilson;S.;Gerald R. Crabtree - 通讯作者:
Gerald R. Crabtree
lnterleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin
白细胞介素 2 介导的 p27Kipl 细胞周期蛋白依赖性激酶抑制剂的消除被雷帕霉素阻止
- DOI:
10.1038/372570a0 - 发表时间:
1994-12-08 - 期刊:
- 影响因子:48.500
- 作者:
Jamison Nourse;Eduardo Firpo;W. Michael Flanagan;Steve Coats;Kornelia Polyak;Mong-Hong Lee;Joan Massague;Gerald R. Crabtree;James M. Roberts - 通讯作者:
James M. Roberts
Signaling via GSK-3 is required during midline skeletogenesis
- DOI:
10.1016/j.ydbio.2006.04.337 - 发表时间:
2006-07-01 - 期刊:
- 影响因子:
- 作者:
Karen J. Liu;Joseph R. Arron;Kryn Stankunas;Gerald R. Crabtree - 通讯作者:
Gerald R. Crabtree
Regulation of the regulators
监管者的监管
- DOI:
10.1038/35040690 - 发表时间:
2000-11-02 - 期刊:
- 影响因子:48.500
- 作者:
Scott Stewart;Gerald R. Crabtree - 通讯作者:
Gerald R. Crabtree
Regulation of the regulators
监管者的监管
- DOI:
10.1038/35040690 - 发表时间:
2000-11-02 - 期刊:
- 影响因子:48.500
- 作者:
Scott Stewart;Gerald R. Crabtree - 通讯作者:
Gerald R. Crabtree
Gerald R. Crabtree的其他文献
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{{ truncateString('Gerald R. Crabtree', 18)}}的其他基金
HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL
劫持癌症驱动者激活 DLBCL 中的促凋亡基因
- 批准号:
10564195 - 财政年份:2022
- 资助金额:
$ 38.73万 - 项目类别:
Small molecule regulation of endogenous transcription factors for circuit-specific neuromodulation
内源转录因子的小分子调节用于电路特异性神经调节
- 批准号:
10260250 - 财政年份:2021
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
9900916 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
8371602 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
9903224 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
9054819 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
8508208 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
ATP-Dependent Chromatin Remodeling in Human Malignancy
人类恶性肿瘤中 ATP 依赖性染色质重塑
- 批准号:
8892817 - 财政年份:2012
- 资助金额:
$ 38.73万 - 项目类别:
Screen for Small Molecule Inhibitors of ATP Dependent Chromatin Remodeling
筛选 ATP 依赖性染色质重塑的小分子抑制剂
- 批准号:
8139341 - 财政年份:2011
- 资助金额:
$ 38.73万 - 项目类别:
Screen for Small Molecule Inhibitors of ATP Dependent Chromatin Remodeling
筛选 ATP 依赖性染色质重塑的小分子抑制剂
- 批准号:
8236903 - 财政年份:2011
- 资助金额:
$ 38.73万 - 项目类别:
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