Elucidation of New Phosphorylation Site of the EWS/ATF1 Fusion Oncoprotein in Clear Cell Sarcoma
透明细胞肉瘤中 EWS/ATF1 融合癌蛋白新磷酸化位点的阐明
基本信息
- 批准号:10513111
- 负责人:
- 金额:$ 7.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsAutomobile DrivingBindingBone TissueC-terminalCell ProliferationCellsChemical AgentsChemicalsChildhoodChimeric ProteinsChromosomal translocationClear Cell SarcomaConserved SequenceCuesCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic AMP-Responsive DNA-Binding ProteinDNA DamageElementsEwings sarcomaFOS geneFusion Oncogene ProteinsGene ExpressionGene FusionGenesGenetic TranscriptionGenotoxic StressGrantGrowth FactorHumanInvestigationMalignant NeoplasmsMediatingMolecularMolecular TargetN-terminalNuclearNuclear ProteinOncogenesOncogenicOncoproteinsPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesPilot ProjectsPlayProtein Binding DomainProtein DephosphorylationProtein KinaseProtein phosphataseProtein-Serine-Threonine KinasesProteinsRoleSiteSomatotropinStimulusSurvival RateTertiary Protein StructureTestingTumor Suppressor Proteinsactivating transcription factoranticancer researchbZIP Domaincancer cellcell growthexperimental studyextracellularhomeodomainmalignant phenotypenovelprogramsresponsesoft tissuetranscription factoryoung adult
项目摘要
Abstract
Clear cell sarcoma (CCS) is an aggressive bone and soft tissue cancer of young adults. It is caused by gene
fusions between EWS (Ewing’s sarcoma oncogene) and ATF1 (activating transcription factor) or CREB
(cAMP-responsive element binding protein), giving rise to chimeric oncoproteins consisting of the N-terminal
EWS domain fused to a C-terminal half of truncated ATF1 and CREB domains. The chimeric EWS/ATF1 and
EWS/CREB oncoproteins are potent transcription factors that bind to CRE (cAMP-responsive element) via the
ATF1 and CREB domains. Normal human ATF1 and CREB are activated by stimulus-induced phosphorylation,
in which ATF1 at Ser63 and CREB at Ser133 are phosphorylated by protein kinase A (PKA) or related kinases
in response to various growth factors and hormones. In contrast, the molecular mechanism through which the
transcription function of EWS/ATF1 and EWS/CREB is regulated remains unknown. The primary reason for
this problem is the fact that truncated ATF1 and CREB domains fused to EWS do not contain these canonical
Ser63 and Ser133 PKA-mediated phosphorylation sites. However, we recently identified the conserved new
phosphorylation sites in the chimeric oncoproteins of ATF1 at Ser198 and CREB at Ser271. Intriguingly, we
found that HIPK2 (homeodomain interacting protein kinase 2), but not PKA, phosphorylates EWS/ATF1 at
Ser198 of the ATF1 domain and suppresses the transcription of c-FOS, one of the key EWS/ATF1 target
genes driving aggressive cell proliferation of CCS. Indeed, EWS/ATF1 can be phosphorylated at Ser198 of the
ATF1 domain in human CCS cells. Furthermore, we preliminary identified candidates of ATF1 Ser198
phosphatases. Thus, we have found two new potential reversible regulators of EWS/ATF1 oncoprotein
through Ser198 phosphorylation. We will test our hypothesis that the phosphorylation status of EWS/ATF1 at
Ser198 determines the EWS/ATF1 transcription activity on key target genes responsible for aggressive
proliferation of CCS cancer cells. We will characterize the phosphorylation and dephosphorylation of
EWS/ATF1 at Ser198 associated with its transcription function and CCS malignant phenotype. As ATF1 and
CREB contain highly conserved phosphorylation sites, we anticipate the same regulatory mechanism of the
EWS/CREB fusion oncoprotein via Ser271 phosphorylation in the truncated CREB domain. HIPK2 as well as
Ser198 ATF1 phosphatases characterized in this proposal can be a new molecular target for more selective
and effective inactivation of these fusion oncoproteins in CCS.
1
摘要
透明细胞肉瘤(CCS)是一种侵袭性骨和软组织癌症的年轻成年人。这是由基因引起的
EWS(尤因肉瘤癌基因)和ATF 1(转录激活因子)或CREB之间的融合
(cAMP-反应元件结合蛋白),产生由N-末端
EWS结构域融合到截短的ATF 1和CREB结构域的C-末端一半。嵌合EWS/ATF 1和
EWS/CREB癌蛋白是有效的转录因子,其通过EWS/CREB结合CRE(cAMP反应元件)。
ATF 1和CREB结构域。正常人ATF 1和CREB通过刺激诱导的磷酸化激活,
其中位于Ser 63的ATF 1和位于Ser 133的CREB被蛋白激酶A(PKA)或相关激酶磷酸化
对各种生长因子和激素的反应。相反,通过分子机制,
EWS/ATF 1和EWS/CREB的转录调控功能尚不清楚。的主要原因
这个问题是与EWS融合的截短的ATF 1和CREB结构域不包含这些典型的
Ser 63和Ser 133 PKA介导的磷酸化位点。然而,我们最近发现了保守的新的
在嵌合癌蛋白ATF 1的Ser 198和CREB的Ser 271的磷酸化位点。有趣的是,我们
发现HIPK 2(同源结构域相互作用蛋白激酶2),而不是PKA,磷酸化EWS/ATF 1,
ATF 1结构域的Ser 198并抑制c-FOS的转录,c-FOS是EWS/ATF 1的关键靶点之一。
基因驱动CCS的细胞增殖。事实上,EWS/ATF 1可以在蛋白质的Ser 198处磷酸化,
人CCS细胞中的ATF 1结构域。此外,我们初步鉴定了ATF 1 Ser 198的候选者,
磷酸酶因此,我们发现了两个新的潜在的EWS/ATF 1癌蛋白可逆调节剂,
Ser 198磷酸化我们将检验我们的假设,即EWS/ATF 1的磷酸化状态在
Ser 198决定了EWS/ATF 1在负责侵袭性肿瘤的关键靶基因上的转录活性。
CCS癌细胞的增殖。我们将描述的磷酸化和去磷酸化的
EWS/ATF 1的Ser 198位点与其转录功能和CCS恶性表型相关。ATF 1和
CREB含有高度保守的磷酸化位点,我们预期CREB的调节机制与CREB的磷酸化位点相同。
EWS/CREB融合癌蛋白通过截短的CREB结构域中的Ser 271磷酸化。HIPK 2以及
Ser 198 ATF 1磷酸酶可以作为一种新的分子靶点,
以及CCS中这些融合癌蛋白的有效失活。
1
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
YOSHIAKI TSUJI其他文献
YOSHIAKI TSUJI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('YOSHIAKI TSUJI', 18)}}的其他基金
Elucidation of New Phosphorylation Site of the EWS/ATF1 Fusion Oncoprotein in Clear Cell Sarcoma
透明细胞肉瘤中 EWS/ATF1 融合癌蛋白新磷酸化位点的阐明
- 批准号:
10670347 - 财政年份:2022
- 资助金额:
$ 7.6万 - 项目类别:
Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics
CREB 在细胞对异生物质的基因毒性反应中的调节和作用
- 批准号:
8540440 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics
CREB 在细胞对异生物质的基因毒性反应中的调节和作用
- 批准号:
8730676 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics
CREB 在细胞对异生物质的基因毒性反应中的调节和作用
- 批准号:
8831225 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics
CREB 在细胞对异生物质的基因毒性反应中的调节和作用
- 批准号:
9114316 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Antioxidant Genes and Oxidative Stress
抗氧化基因和氧化应激的调节
- 批准号:
8442949 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Antioxidant Genes and Oxidative Stress
抗氧化基因和氧化应激的调节
- 批准号:
8241907 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics
CREB 在细胞对异生物质的基因毒性反应中的调节和作用
- 批准号:
8185590 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Antioxidant Genes and Oxidative Stress
抗氧化基因和氧化应激的调节
- 批准号:
8107277 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Antioxidant Genes and Oxidative Stress
抗氧化基因和氧化应激的调节
- 批准号:
8629765 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 7.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 7.6万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 7.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)