Mdm2 Alternative Splicing in DNA Damage and Cancer
Mdm2 选择性剪接在 DNA 损伤和癌症中的作用
基本信息
- 批准号:10738347
- 负责人:
- 金额:$ 6.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAlanine TransaminaseAlternative SplicingAntineoplastic AgentsAstrocytomaAutomobile DrivingBindingBinding ProteinsBioinformaticsBiological AssayBiologyBiophysicsBreastCancer BiologyCell LineCell ProliferationCellsCellular StressChemistryChildhood GliomaComplexCoupledDNA DamageDataDiseaseDominant-Negative MutationEngineeringEventExcisionExonsFutureGenerationsGenesGenetically Engineered MouseGenomeGenotoxic StressGliomaGoalsHigh-Throughput Nucleotide SequencingHumanIn VitroKnowledgeLengthLungLymphomaMDM2 geneMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresMechanicsMediatingMethodologyMethodsMicroRNAsModalityModelingMolecularMusMutationNuclearNuclear ProteinNuclear RNAOligonucleotidesOncogenicOutcomeOvaryPathway interactionsPharmacologic SubstancePhenotypePlayPositioning AttributePrimary NeoplasmPropertyProtein IsoformsProteinsPublishingRNARNA BiochemistryRNA ProcessingRNA SequencesRNA SplicingRNA metabolismRNA-Binding ProteinsRegulationRegulatory ElementRepressionResearchRhabdomyosarcomaRoleSamplingStressSystemTP53 geneTechnologyTestingTherapeuticTherapeutic InterventionTumor Suppressor ProteinsVariantViralWorkXenograft procedurecancer therapycancer typecell growthcell typechemotherapeutic agentcombinatorialdesigndrug discoveryexon skippinggenotoxicityindustry partnerliposarcomamRNA Precursormouse modelnovelnovel therapeutic interventionoverexpressionpreventresponsetherapy designtumortumor progressiontumorigenesistumorigenic
项目摘要
ABSTRACT
Tumor suppressor p53 is the quintessential guardian of the genome whose function is inhibited in greater than
50% of all human cancers. Though mutation and deletion of p53 are major contributors to p53 inactivation,
overexpression of the negative regulators MDM2 and MDM4 (MDMX) are also known to inactivate p53, thus
leading to the cancer phenotype. Our lab has shown that specific types of cell stress initiate the generation of
an alternatively spliced isoform of MDM2. The predominant MDM2 alternative isoform, MDM2-ALT1 also
known as MDM2-B, functions to primarily activate the p53 pathway by inhibiting MDM2 and MDM4 in a
dominant negative fashion. Paradoxically, this isoform is upregulated in several human cancers, such as
pediatric high-grade gliomas, astrocytomas, rhabdomyosarcomas (RMS), and liposarcomas, as well as adult
cancers such as lymphomas and those of the breast. Thus, MDM2-ALT1 plays opposing roles in cancer
progression dependent upon the context of its expression. In the proposed research, we will study the
underpinnings of the control of the p53 pathway by MDM2-ALT1 to better understand 1) the specific
mechanism by which that MDM2-ALT1 is generated in cancer and 2) the ability of the resultant isoforms to be
targeted using splice-switching oligonucleotides. We hypothesize that the expression of oncogenic MDM2-
ALT1 is modulated by alterations in protein and RNA nuclear factors during the progression to tumorigenesis
and can be targeted to induce splicing changes. We will use assays that identify and measure splice regulation
in conjunction with gene editing approaches to identify RNA sequences and their respective nuclear factor-
binding partners necessary for regulation of MDM2 splicing. Furthermore, we will use novel genetically
engineered mouse models as well as established mouse xenograft assays and novel splice switching
oligonucleotides (SSOs) to modulate MDM2 isoform levels. Our work will broaden our knowledge of
combinatorial regulation of RNA processing in response to stress and in cancer and interrogate the utility of
MDM2 isoforms modulation for rational control of the p53 pathway.
摘要
抑癌基因P53是基因组的典型守护者,其功能被抑制的程度超过
占所有人类癌症的50%。虽然P53的突变和缺失是P53失活的主要原因,
负调控基因MDM2和MDM4(MDMX)的过度表达也可以使P53失活,因此
导致癌症表型。我们的实验室已经表明,特定类型的细胞应激启动了
MDM2的另一种剪接异构体。主要的MDM2替代亚型MDM2-ALT1还
被称为MDM2-B的作用主要是通过抑制MDM2和MDM4激活P53通路。
占主导地位的负面时尚。矛盾的是,这种异构体在几种人类癌症中表达上调,例如
儿童高级别胶质瘤、星形细胞瘤、横纹肌肉瘤和脂肪肉瘤,以及成人
淋巴瘤和乳腺癌等癌症。因此,MDM2-ALT1在癌症中扮演相反的角色
行进取决于其表达的上下文。在建议的研究中,我们会研究
MDM2-ALT1控制P53通路的基础以更好地理解1)特异性
MDM2-ALT1在癌症中产生机制和2)生成的异构体的能力
靶向使用剪接开关寡核苷酸。我们假设致癌MDM2的表达-
ALT1在肿瘤发生过程中受蛋白质和RNA核因子变化的调节
并且可以被靶向地诱导剪接变化。我们将使用识别和测量剪接调控的分析方法
结合基因编辑方法来识别RNA序列及其各自的核因子-
MDM2剪接调控所需的结合伙伴。此外,我们将从基因上使用小说
工程小鼠模型以及已建立的小鼠异种移植试验和新的剪接切换
调节MDM2亚型水平的寡核苷酸(SSO)。我们的工作将拓宽我们对
RNA加工在应激反应和癌症中的组合调节,并询问
MDM2异构体调控P53通路的合理调控。
项目成果
期刊论文数量(0)
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Dawn S Chandler其他文献
Dawn S Chandler的其他文献
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{{ truncateString('Dawn S Chandler', 18)}}的其他基金
Diversity Supplement R01----Mdm2 Alternative Splicing in DNA Damage and Cancer
多样性补充剂 R01----Mdm2 选择性剪接在 DNA 损伤和癌症中的作用
- 批准号:
10599711 - 财政年份:2021
- 资助金额:
$ 6.53万 - 项目类别:
A new mouse model for testing splice-switching therapies in IGF-driven cancers
用于测试 IGF 驱动癌症中剪接转换疗法的新小鼠模型
- 批准号:
10373088 - 财政年份:2021
- 资助金额:
$ 6.53万 - 项目类别:
A new mouse model for testing splice-switching therapies in IGF-driven cancers
用于测试 IGF 驱动癌症中剪接转换疗法的新小鼠模型
- 批准号:
10202220 - 财政年份:2021
- 资助金额:
$ 6.53万 - 项目类别:
Mdm2 Alternative Splicing in DNA Damage and Cancer
Mdm2 选择性剪接在 DNA 损伤和癌症中的作用
- 批准号:
10280391 - 财政年份:2021
- 资助金额:
$ 6.53万 - 项目类别:
Mdm2 Alternative Splicing in DNA Damage and Cancer
Mdm2 选择性剪接在 DNA 损伤和癌症中的作用
- 批准号:
10475187 - 财政年份:2021
- 资助金额:
$ 6.53万 - 项目类别:
Targeting insulin receptor splicing for treatment of rhabdomyosarcoma
靶向胰岛素受体剪接治疗横纹肌肉瘤
- 批准号:
9100118 - 财政年份:2016
- 资助金额:
$ 6.53万 - 项目类别:
Using TSUNAMI in a sensitized mouse to generate an intermediate SMA model
在致敏小鼠中使用 TSUNAMI 生成中间 SMA 模型
- 批准号:
8772680 - 财政年份:2014
- 资助金额:
$ 6.53万 - 项目类别:
Coordinately regulated alternative splicing in DNA damage and cancer
DNA 损伤和癌症中协调调节的选择性剪接
- 批准号:
8447373 - 财政年份:2010
- 资助金额:
$ 6.53万 - 项目类别:
Coordinately regulated alternative splicing in DNA damage and cancer
DNA 损伤和癌症中协调调节的选择性剪接
- 批准号:
8608489 - 财政年份:2010
- 资助金额:
$ 6.53万 - 项目类别:
Coordinately regulated alternative splicing in DNA damage and cancer
DNA 损伤和癌症中协调调节的选择性剪接
- 批准号:
7890944 - 财政年份:2010
- 资助金额:
$ 6.53万 - 项目类别: