Role of SETD5 in Chromatin Regulation and Tumorigenesis
SETD5 在染色质调节和肿瘤发生中的作用
基本信息
- 批准号:10586057
- 负责人:
- 金额:$ 37.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AttenuatedBiochemicalCRISPR/Cas technologyCancer BiologyCancer EtiologyCancer ModelCancer cell lineCellsChromatinClassificationComplexDevelopmentDrug resistanceEnzymesEpigenetic ProcessEtiologyExcisionFoundationsGene DeliveryGenesGeneticGenetic ScreeningGenomeGoalsGrowthHistonesHumanIntellectual functioning disabilityKRAS2 geneKnowledgeLaboratoriesLinkLiteratureLung AdenocarcinomaLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMammalian CellMethylationMethyltransferaseModelingModificationMolecularMusMutateMutationNuclearOncogenesOncogenicOrphanPancreatic Ductal AdenocarcinomaPathogenesisPathologicPathway interactionsPatientsPharmaceutical PreparationsPhysiologicalPost-Translational Protein ProcessingProliferatingProtein KinaseProteinsProteomeProteomicsRegulationRoleSET DomainSignal PathwaySignal TransductionSubstrate SpecificityTechniquesTertiary Protein StructureTestingTherapeuticWorkXenograft Modelautism spectrum disordercancer cellcell behaviorcell transformationcomplement systemdevelopmental diseasedrug developmentdruggable targetepigenetic silencingexperimental studygenetic corepressorgenome editinghuman cancer mouse modelhuman tissuein vitro activityin vivoinhibitorlung cancer cellmouse modelmultidisciplinarymutantnovel therapeutic interventionpancreatic PDX modelspancreatic cancer cellspancreatic cancer modelpancreatic ductal adenocarcinoma modelpatient derived xenograft modelprogramstherapeutic candidatetherapeutic targettranslational approachtumortumorigenesistumorigenic
项目摘要
ABSTRACT
Our overarching goal is to better understand the role of post-translational modifications (PTMs) of cellular
proteins in cancer with the underlying assumption that the enzymes that catalyze the addition or the removal of
these PTMs are candidate therapeutic targets in cancer. While enzymes such as protein kinases have been
extensively studied in cancer, new classes of enzymes have recently emerged as potential cancer targets. In
particular, more than 100 lysine methyltransferases (KMTs) are predicted to be present in the human proteome
and many are implicated in cancer etiology. However, the catalytic activity and substrate specificity for many of
these enzymes remains unknown. A central hypothesis to be tested here is that uncovering the function of
orphan KMTs may provide new links between protein lysine methylation signaling and cancer biology.
Here we focus on the candidate KMT SETD5 (SET domain protein 5) as a potential critical regulator of
tumorigenesis. SETD5 mutations are involved in the etiology of intellectual disabilities and autism spectrum
disorders. SETD5 has also been implicated in influencing tumors harboring activating mutations in the KRAS
oncogene, such as pancreas cancer. However, SETD5 is an orphan enzyme and knowledge of any potential
endogenous substrates and the overall mode of action of this candidate enzyme in cells and in vivo is obscure.
Based on preliminary observations, we hypothesize that SETD5, via regulation of chromatin dynamics,
governs epigenetic programs important for normal cellular behaviors and promotes tumorigenesis.
The goal of Aim 1 is to elucidate the physiologic catalytic activity of SETD5 and molecular functions of
SETD5 at chromatin. We also will investigate SETD5 interacting partners and mechanisms of targeting SETD5
to the genome. In Aim 2 we characterize the role of SETD5 in tumors driven by oncogenic RAS pathway. We
will test the hypothesis that SETD5 cooperates with RAS signaling to promote the unlimited expansion of
cancer cells in vivo using mouse models of Pancreas Ductal Adenocarcinoma and Lung Adenocarcinoma, two
most lethal human cancers in which KRAS is frequently activated. We will also investigate the tumorigenic role
of SETD5 in human tissue using patient-derived xenograft pancreatic and lung cancer models and explore
SETD5 as a potential therapeutic target. Finally, we focus on the mode of action of SETD5 in cancer in cells
and in vivo. We will use cutting-edge gene delivery techniques to genetically modify pancreatic cancer in vivo.
A long-term goal is to evaluate SETD5 as a relevant and druggable target for the treatment of lethal cancers.
抽象的
我们的首要目标是更好地了解细胞翻译后修饰 (PTM) 的作用
癌症中的蛋白质,其基本假设是催化添加或去除蛋白质的酶
这些 PTM 是癌症的候选治疗靶点。虽然蛋白激酶等酶已被
经过对癌症的广泛研究,新一类酶最近已成为潜在的癌症靶点。在
特别是,预计人类蛋白质组中存在超过 100 种赖氨酸甲基转移酶 (KMT)
许多与癌症病因有关。然而,许多的催化活性和底物特异性
这些酶仍然未知。这里要测试的一个中心假设是揭示
孤儿 KMT 可能提供蛋白质赖氨酸甲基化信号传导与癌症生物学之间的新联系。
在这里,我们重点关注候选 KMT SETD5(SET 结构域蛋白 5)作为潜在的关键调节因子
肿瘤发生。 SETD5 突变与智力障碍和自闭症谱系的病因有关
失调。 SETD5 还与影响具有 KRAS 激活突变的肿瘤有关
癌基因,例如胰腺癌。然而,SETD5 是一种孤儿酶,并且了解任何潜在的酶
内源性底物以及该候选酶在细胞和体内的总体作用模式尚不清楚。
根据初步观察,我们假设 SETD5 通过调节染色质动力学,
控制对正常细胞行为重要的表观遗传程序并促进肿瘤发生。
目标 1 的目标是阐明 SETD5 的生理催化活性和 SETD5 的分子功能
SETD5 位于染色质。我们还将研究 SETD5 的交互伙伴和针对 SETD5 的机制
到基因组。在目标 2 中,我们描述了 SETD5 在致癌 RAS 通路驱动的肿瘤中的作用。我们
将检验SETD5配合RAS信令促进无限扩展的假设
使用胰腺导管腺癌和肺腺癌(两种)小鼠模型进行体内癌细胞
KRAS 经常被激活的最致命的人类癌症。我们还将研究致瘤作用
使用患者来源的异种移植胰腺癌和肺癌模型检测人体组织中的 SETD5 并探索
SETD5作为潜在的治疗靶点。最后,我们重点关注SETD5在细胞癌中的作用方式
和体内。我们将使用尖端的基因传递技术对体内胰腺癌进行基因改造。
长期目标是评估 SETD5 作为治疗致命癌症的相关且可药物化的靶点。
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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Pawel K. Mazur其他文献
An integrative cross-tumors approach identifies FOSL1 as an oncogene dependency in KRAS-driven lung cancer
- DOI:
10.1016/j.jtho.2015.12.084 - 发表时间:
2016-02-01 - 期刊:
- 影响因子:
- 作者:
Adrian Vallejo;Naiara Perurena;Elizabeth Guruceaga;Pawel K. Mazur;Susana Martinez-Canarias;Carolina Zandueta;Dana Gwinn;Leanne C. Sayles;Chen-Hua Chuang;Jesper B. Andersen;Aline Bozec;Alejandro Sweet-Cordero;Julien Sage;Fernando Lecanda;Silvestre Vicent - 通讯作者:
Silvestre Vicent
ASIC – LIVER , PANCREAS , AND BILIARY RACT otch Signaling Is Required for Exocrine Regeneration After cute Pancreatitis
ASIC – 肝脏、胰腺和胆管 otch 信号是可爱胰腺炎后外分泌再生所必需的
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Ens T. Siveke;C. L. –. Martellato;Marcel Lee;Pawel K. Mazur;H. Nakhai;R. Radtke;R. Schmid - 通讯作者:
R. Schmid
Pawel K. Mazur的其他文献
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{{ truncateString('Pawel K. Mazur', 18)}}的其他基金
Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance
胃癌进展和治疗耐药中的肿瘤细胞谱系多样性和组成
- 批准号:
10662203 - 财政年份:2022
- 资助金额:
$ 37.83万 - 项目类别:
Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance
胃癌进展和治疗耐药中的肿瘤细胞谱系多样性和组成
- 批准号:
10342536 - 财政年份:2022
- 资助金额:
$ 37.83万 - 项目类别:
Role of SETD5 in Chromatin Regulation and Tumorigenesis
SETD5 在染色质调节和肿瘤发生中的作用
- 批准号:
10429907 - 财政年份:2019
- 资助金额:
$ 37.83万 - 项目类别:
The SMYD3-ERK5 signaling module in pancreatic cancer
胰腺癌中的 SMYD3-ERK5 信号模块
- 批准号:
8950606 - 财政年份:2015
- 资助金额:
$ 37.83万 - 项目类别:
The SMYD3-ERK5 signaling module in pancreatic cancer
胰腺癌中的 SMYD3-ERK5 信号模块
- 批准号:
9128576 - 财政年份:2015
- 资助金额:
$ 37.83万 - 项目类别:
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