Negative MAPK-RAS-ERK pathway regulation to sustain CIC-DUX4 expression
负 MAPK-RAS-ERK 通路调节维持 CIC-DUX4 表达
基本信息
- 批准号:10818281
- 负责人:
- 金额:$ 7.52万
- 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:2021-06-17 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescentBindingBiochemicalBiological AssayCell DeathCellsChIP-seqChildChildhoodChimeric ProteinsClinicalDNADUSP6 proteinDataData SetEnsureFamily memberFusion Oncogene ProteinsGeneticGenetic TranscriptionGuanosine TriphosphateHyperactivityLinkMAP Kinase GeneMalignant - descriptorMalignant NeoplasmsMediatingMolecularNuclear ExportOncoproteinsOutcomePathway AnalysisPathway interactionsPatientsPhosphoric Monoester HydrolasesPhosphorylationPlasmidsProcessProtein FamilyRegulationRoleSignal TransductionSmall Interfering RNATherapeuticTranscriptional RegulationUndifferentiatedcandidate identificationeffective therapyexperimental studyfusion geneineffective therapiesinsightknock-downneoplastic celloverexpressionparent grantparent projectpharmacologicprotein degradationresponsesarcomasmall hairpin RNAtherapeutic targettranscription factortranscriptomicstumorigenesisyoung adult
项目摘要
Project Summary/Abstract
Transcription factor (TF) fusion genes create oncoproteins that drive tumorigenesis. While TF fusions
represent cancer specific alterations, direct therapeutic targeting remains a clinical challenge. One
example is the CIC-DUX4 TF fusion which defines an aggressive subset of round cell sarcoma in
children and young adults. The clinical outcomes for CIC-DUX4 patients remain dismal due to high
metastatic propensity and ineffective therapies. Currently, no therapies exist that direclty target the CIC-
DUX4 fusion. To meet this need, we have recently identified a mechanistic link between the terminal
MAPK signaling substrate, ERK, and CIC-DUX4. Specifically, ERK physically binds and phosphorylates
CIC-DUX4 leading to rapid nuclear export, degradation of the fusion, and tumor cell death. Since MAPK
signaling is a ubiquitous pathway expressed in both normal and malignant processes, we wondered
how the CIC-DUX4 fusion could maintain its own expression. Through biochemical and molecular
studies we have identified a key role for negative MAPK-ERK regulation in CIC-DUX4 sarcoma cells.
Whereby, CIC-DUX4 transcriptionally upregulates the ERK specific phosphatase, DUSP6, to limit ERK
activity and thus enable CIC-DUX4 expression. More recently, we made an unexpected finding that
CIC-DUX4 expression could also downregulate RAS activity. Since RAS is a proximal MAPK substrate
not targeted by DUSP6, we hypothesized that CIC-DUX4 was limiting MAPK-RAS-ERK signaling flux
at multiple levels within this canonical signaling cascade. This proposal will define how CIC-DUX4 is
regulating RAS activity, thus further sustaining CIC-DUX4 expression.
项目摘要/摘要
转录因子(TF)融合基因产生驱动肿瘤发生的癌蛋白。而TF融合
代表癌症特异性改变,直接治疗靶向仍然是一个临床挑战。一
例如CIC-DUX4 Tf融合,它定义了圆形细胞肉瘤的侵袭性亚群
儿童和年轻人。CIC-DUX4患者的临床结果仍然令人沮丧,因为
转移倾向和无效的治疗方法。目前,还没有直接针对CIC的治疗方法-
DUX4融合。为了满足这一需求,我们最近确定了航站楼之间的机械连接
MAPK信号底物、ERK和CIC-DUX4。具体来说,ERK在物理上结合并磷酸化
CIC-DUX4导致核快速输出,融合降解,肿瘤细胞死亡。自MAPK以来
我们想知道,信号是一种在正常和恶性过程中表达的普遍途径。
CIC-DUX4融合蛋白如何维持自身表达。通过生物化学和分子生物学
研究表明,MAPK-ERK负性调控在CIC-DUX4肉瘤细胞中起关键作用。
因此,CIC-DUX4转录上调ERK特异性磷酸酶DUSP6,以限制ERK
活性,从而启动CIC-DUX4的表达。最近,我们有一个意想不到的发现
CIC-DUX4的表达也可下调RAS活性。由于RAS是近端MAPK底物
不是DUSP6的目标,我们假设CIC-DUX4限制了MAPK-RAS-ERK信号流
在这个规范的信号级联中的多个级别。该提案将定义CIC-DUX4如何
调节RAS活性,从而进一步维持CIC-DUX4的表达。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.
- DOI:10.1016/j.celrep.2022.111443
- 发表时间:2022-10-04
- 期刊:
- 影响因子:8.8
- 作者:Won Kim, Ji;Luck, Cuyler;Wu, Wei;Ponce, Rovingaile Kriska;Lin, Yone Kawe;Gupta, Nehal;Okimoto, Ross A.
- 通讯作者:Okimoto, Ross A.
WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma.
- DOI:10.1172/jci.insight.152293
- 发表时间:2022-03-22
- 期刊:
- 影响因子:8
- 作者:Ponce RKM;Thomas NJ;Bui NQ;Kondo T;Okimoto RA
- 通讯作者:Okimoto RA
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Ross Okimoto其他文献
Ross Okimoto的其他文献
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{{ truncateString('Ross Okimoto', 18)}}的其他基金
Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas
未分化肉瘤中 Capicua (CIC) 融合癌蛋白的治疗性降解
- 批准号:
10299485 - 财政年份:2021
- 资助金额:
$ 7.52万 - 项目类别:
Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas
未分化肉瘤中 Capicua (CIC) 融合癌蛋白的治疗性降解
- 批准号:
10434138 - 财政年份:2021
- 资助金额:
$ 7.52万 - 项目类别:
Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas
未分化肉瘤中 Capicua (CIC) 融合癌蛋白的治疗性降解
- 批准号:
10627800 - 财政年份:2021
- 资助金额:
$ 7.52万 - 项目类别:
Therapeutic rescue of the transcriptional repressor Capicua to inhibit lung cancer metastasis
转录抑制因子 Capicua 抑制肺癌转移的治疗拯救
- 批准号:
10328925 - 财政年份:2018
- 资助金额:
$ 7.52万 - 项目类别:
Therapeutic rescue of the transcriptional repressor Capicua to inhibit lung cancer metastasis
转录抑制因子 Capicua 抑制肺癌转移的治疗拯救
- 批准号:
10082441 - 财政年份:2018
- 资助金额:
$ 7.52万 - 项目类别:
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