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
透明细胞肉瘤是一种发生在青壮年的侵袭性骨和软组织癌。它是由基因引起的
尤文氏肉瘤癌基因EWS与激活转录因子ATF1或CREB的融合
(cAMP反应元件结合蛋白),产生由N-末端组成的嵌合癌蛋白
EWS结构域与截短的atf1和CREB结构域的C-末端一半融合。嵌合EWS/atf1和
EWS/CREB癌蛋白是一种有效的转录因子,通过与cAMP反应元件结合。
ATF1和CREB结构域。正常人ATF1和CREB被刺激诱导的磷酸化激活,
其中Ser63处atf1和Ser133处的CREB被蛋白激酶A(PKA)或相关的激酶磷酸化
对各种生长因子和荷尔蒙作出反应。相比之下,分子机制通过这些机制
EWS/atf1和EWS/CREB的转录功能是否受到调控仍不清楚。其主要原因是
这个问题是这样一个事实:融合到EWS的截断的atf1和creb结构域不包含这些规范的
Ser63和Ser133是由Ser63和Ser133介导的PKA磷酸化位点。然而,我们最近确定了保守的新
Atf1在Ser198位和CREB在Ser271位的嵌合癌蛋白的磷酸化位点。有趣的是,我们
发现HIPK2(同源结构域相互作用蛋白激酶2),而不是PKA,使EWS/atf1在
Ser198,并抑制关键的EWS/atf1靶基因之一c-fos的转录
驱动CCS侵袭性细胞增殖的基因。事实上,EWS/atf1可以在第198位被磷酸化。
人CCS细胞中的ATF1结构域。此外,我们初步确定了atf1ser198的候选者。
磷酸酶。因此,我们发现了两个新的潜在的ews/atf1癌蛋白可逆调节因子。
通过Ser198的磷酸化。我们将检验我们的假设,即EWS/ATF1的磷酸化状态在
Ser198决定EWS/atf1在负责攻击的关键靶基因上的转录活性
CCS癌细胞增殖情况。我们将表征蛋白的磷酸化和去磷酸化。
EWS/atf1基因Ser198位与其转录功能及CCS恶性表型相关。作为atf1和
CREB含有高度保守的磷酸化位点,我们预计与CREB的调节机制相同
截短CREB结构域中Ser271磷酸化的EWS/CREB融合癌蛋白。HIPK2以及
Ser198 atf1磷酸酶可作为选择性更强的新的分子靶点
并在CCS中有效地灭活这些融合癌蛋白。
1
项目成果
期刊论文数量(0)
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YOSHIAKI TSUJI其他文献
YOSHIAKI TSUJI的其他文献
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{{ 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:
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