Function and Mechanism of TET Regulation of Tumor Immunity
TET调节肿瘤免疫的功能及机制
基本信息
- 批准号:10020932
- 负责人:
- 金额:$ 31.94万
- 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:2012-03-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectBindingChromatinChronicCytokine SignalingDNADNA Modification ProcessDevelopmentDioxygenasesEnzymesEpigenetic ProcessFamilyFoundationsFumaratesFundingGene ActivationGene ExpressionGenesHIVHematopoietic NeoplasmsHistone DeacetylaseHumanHypermethylationImmunotherapyImpairmentInflammationInflammatoryInterferonsInterleukin-6Intrahepatic CholangiocarcinomaInvestigationIsocitrate DehydrogenaseLiverLymphomagenesisMalignant NeoplasmsMediatingMetabolicMethylationMouse StrainsMusMutationNFKB Signaling PathwayPathogenesisPathway interactionsPlayPrimary NeoplasmProductionProteinsRecurrent tumorRegulationResistanceResolutionRoleSeriesSignal PathwaySignal TransductionSolid NeoplasmStructureSuccinatesSuggestionTechnologyTestingTherapeuticTumor ImmunityTumor SuppressionTumor-DerivedTumor-infiltrating immune cellsWT1 genealpha ketoglutaratebasecancer genomicschemokinecytokinedemethylationdesigngene discoverygene repressiongenetic analysishistone demethylasehistone modificationimprovedin vivoloss of function mutationmembermutantneoplasm immunotherapynovelpromoterrecruitresponsetranscription factortumorubiquitin-protein ligasevpr Gene Products
项目摘要
Project Abstract
Nearly half of newly discovered cancer driver genes discovered by the cancer genomic studies encode proteins
involved in histone or DNA modification, including the TET family of DNA dioxygenases. Loss-of-function
mutations in TET genes occur early and frequently in human hematopoietic malignancy. Mutations in TET genes,
however, are uncommon in solid tumors. Instead, TET activity is significantly reduced in different types of human
tumors. We do not know the significance of decreased TET activity in solid tumors. In this study, we hypothesize
that TET has a previously unrecognized key function in both the JAK-STAT and NF-κ pathways. Inactivation of
TET in results in chronic tumor-promoting inflammation and escape from anti-tumor immunity. Thus, stimulating
TET activity represents a viable opportunity to enhance antitumor immunity and to improve immunotherapy. We
will test this hypothesis by defining the following aspects of TET2 activity: The function and mechanism of
TET2 in the JAK-STAT pathway and in tumor immunity (Aim 1); The regulation of TET2 and tumor
immunity by reversible monoubiquitylation (Aim 2); and The catalytically independent function and
mechanism of TET2 in tumor suppression (Aim 3).
During the past funding period, we have made the following discoveries that significantly affect the TET
field and that form the foundation for this investigation: (1) Multiple oncometabolites produced or accumulated by
mutations in different metabolic enzymes act as antagonists α-ketoglutarate (αKG) and inhibit multiple αKG-
dependent enzymes, including TET enzymes. (2) TET activity is dynamically regulated in vivo. (3) Development
of solid tumors of many different types is associated with a substantial decrease in TET activity. (4) TET is
reversibly monoubiquitylated by CRL4VprBP E3 ligase and UPS15 deubiquitylase, enhancing and impairing TET
activity, respectively. This regulation is disrupted by multiple recurrent tumor-derived mutations in TET2. (5) HIV
protein Vpr reprograms CRL4VprBP E3 ligase to catalyze polyubiquitylation and degradation of TET proteins to
sustain the expression of pro-inflammatory cytokine and promote HIV pathogenesis. (6) Multiple sequence-
specific transcription factors (TFs) recruit TET2 to their target genes, including members of NF-κB and STAT
families. (7) Loss of TET2 function in tumors impairs interferon signaling, chemokine production, and T cell
infiltration, and confers resistance to tumor immunity and immunotherapy.
This investigation is built on our pioneering and extensive study of the then newly discovered TET
enzymes. It will investigate a novel aspect of cytokine signaling and tumor immunity regulation—by TET-
mediated DNA demethylation. It will use newly developed technology and mouse strains to determine how TET
proteins regulate gene expression by catalytically-dependent and -independent mechanisms. It will explore a
novel regulation of TET by reversible monoubiquitylation and the therapeutic opportunity of this regulation. This
investigation represents the first exploration on the function and mechanism of TET in tumor immunity.
项目摘要
癌症基因组研究发现的近一半新发现的癌症驱动基因编码蛋白质
参与组蛋白或DNA修饰,包括DNA双加氧酶的泰特家族。功能丧失
泰特基因的突变在人造血系统恶性肿瘤中早期和频繁发生。泰特基因突变,
然而,在实体瘤中并不常见。相反,泰特活性在不同类型的人中显著降低,
肿瘤的我们不知道实体瘤中泰特活性降低的意义。在这项研究中,我们假设
泰特在JAK-STAT和NF-κ途径中都具有以前未被认识到的关键功能。失活
泰特导致慢性肿瘤促进性炎症和逃避抗肿瘤免疫。因此,刺激
泰特活性代表了增强抗肿瘤免疫和改善免疫疗法的可行机会。我们
将通过定义TET 2活性的以下方面来测试这一假设:
TET 2在JAK-STAT通路和肿瘤免疫中的作用(目的1); TET 2与肿瘤免疫的调节
通过可逆的单泛素化免疫(目的2);和催化独立的功能和
TET 2抑制肿瘤的机制(目的3)。
在过去的资助期间,我们发现了以下显著影响泰特的发现
本研究的基础是:(1)多种癌细胞产生或积累,
不同代谢酶中的突变可作为α-酮戊二酸(αKG)拮抗剂,并抑制多种αKG-
依赖性酶,包括泰特酶。(2)泰特活性在体内是动态调节的。(3)发展
许多不同类型的实体瘤的发生与泰特活性的显著降低有关。(4)泰特是
被CRL 4 VprBP E3连接酶和UPS 15去泛素化酶可逆地单泛素化,增强和损害泰特
活动,分别。这种调节被TET 2中的多个复发性肿瘤衍生突变破坏。(5)艾滋病毒
蛋白Vpr重编程CRL 4 VprBP E3连接酶以催化泰特蛋白的多聚泛素化和降解,
维持促炎细胞因子的表达并促进HIV发病。(6)多重序列-
特异性转录因子(TF)将TET 2募集到其靶基因,包括NF-κB和STAT成员
家庭(7)肿瘤中TET 2功能的丧失损害干扰素信号传导、趋化因子产生和T细胞增殖。
浸润,并赋予对肿瘤免疫和免疫疗法的抗性。
这项研究是建立在我们对当时新发现的泰特的开创性和广泛研究的基础上的
内切酶本研究将探讨细胞因子信号转导和肿瘤免疫调节的新方面--通过泰特--
介导的DNA去甲基化。它将使用新开发的技术和小鼠品系,以确定如何泰特
蛋白质通过催化依赖性和非催化依赖性机制调节基因表达。它将探索一个
通过可逆的单泛素化对泰特的新调节以及这种调节的治疗机会。这
本研究首次探讨了泰特在肿瘤免疫中的作用及机制。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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ALBERT Sidney BALDWIN其他文献
ALBERT Sidney BALDWIN的其他文献
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{{ truncateString('ALBERT Sidney BALDWIN', 18)}}的其他基金
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