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:9900916
- 负责人:
- 金额:$ 21.2万
- 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 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:ATPase DomainAmino AcidsBindingBiologicalBiological AssayCharacteristicsChromatinComplexDependenceDevelopmentGene DeletionGenesGenetic RecombinationGenetic TranscriptionGenetic studyGenomeGrantHumanHuman GeneticsInvestigationKineticsLaboratoriesMalignant NeoplasmsMediatingMissense MutationMolecularMutationNatureNormal CellOncogenicPRC1 ProteinPatternPharmaceutical PreparationsPlayPolycombProductionProteinsRecurrenceRepressionRoleSpecificitySurfaceSystemTechniquesTherapeuticTumor Suppressor ProteinsWorkbasecancer cellchromatin remodelingcombinatorialdesignearly screeningexome sequencingin vivoinhibitor/antagonistnovelrepairedsmall moleculetooltumortumorigenesis
项目摘要
ABSTRACT
Recent exome sequencing studies have found that over 20% of human cancers have deleterious mutations in
the genes encoding the subunits of mSWI/SNF (BAF) complexes. A much larger number of tumors have
amplifications or deletions of these genes. These complexes are polymorphic assemblies of 15 subunits
encoded by 28 genes giving rise to remarkable combinatorial specificity. This biologic specificity is reflected in
the highly selective pattern of oncogenic mutations in specific subunits in specific cancers. Cancer mutations
generally have the characteristics of tumor suppressors and are generally heterozygous, implying that they
play a genetically dominant role in suppressing tumor formation. Work in our lab and others has led to the
conclusion that the ability of these complexes to oppose polycomb-mediated repression contributes to their
roles in both development and oncogenesis. Hence, we will focus our work on the mechanisms underlying the
opposition between BAF and polycomb and its therapeutic consequences. First we will use a novel, newly
designed in vivo chromatin remodeling assay to fully characterize the nature of the opposition on a minute-by-
minute basis. Secondly, we will define the energetic requirements for BAF-polycomb opposition and the
essential role of ATP in regulating binding and release of PRC1 from BAF. Third, we will fully characterize the
direct interaction between BAF and polycomb repressive complex 1 (PRC1) in terms of subunits and domains
that are essential for this interaction. Fourth, we will explore the consequences of disruption of BAF-polycomb
opposition for repair, recombination and transcription over the genome. Finally, we will define the therapeutic
potential of a group of small molecule BAF inhibitors that we identified in earlier screens. At the conclusion of
these studies we should have a mechanistic understanding of BAF-polycomb opposition and have explored at
least two potential paths for the production of cancer-specific drugs.
摘要
最近的外显子组测序研究发现,超过20%的人类癌症在外显子组中具有有害突变。
编码mSWI/SNF(BAF)复合物亚基的基因。更多的肿瘤
这些基因的扩增或缺失。这些复合物是由15个亚基组成的多态性组装体
由28个基因编码,产生显着的组合特异性。这种生物特异性反映在
特定癌症中特定亚单位的致癌突变的高度选择性模式。癌症突变
通常具有肿瘤抑制因子的特征,并且通常是杂合的,这意味着它们
在抑制肿瘤形成中起遗传主导作用。我们实验室和其他人的工作导致了
结论这些复合物的能力,以反对polycomb介导的镇压有助于他们
在发育和肿瘤发生中的作用。因此,我们将把工作重点放在
BAF和polycomb之间的对立及其治疗后果。首先,我们将使用一个新的,
设计了体内染色质重塑试验,以充分表征分钟的对立性质,
分钟的基础上。其次,我们将定义BAF-polycomb反对派的能量要求,
ATP在调节BAF结合和释放PRC 1中的重要作用。第三,我们将全面描述
BAF和多梳阻遏复合物1(PRC 1)在亚基和结构域方面的直接相互作用
对这种互动至关重要。第四,我们将探讨BAF-polycomb中断的后果
修复、重组和转录的对立。最后,我们将定义治疗
这是我们在早期筛选中发现的一组小分子BAF抑制剂的潜力。结束时
这些研究,我们应该有一个机械的理解BAF polycomb反对,并探讨了在
至少有两条潜在的生产癌症特异性药物的途径。
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:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 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:
10586587 - 财政年份:2012
- 资助金额:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 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:
$ 21.2万 - 项目类别:
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