HTLV-I Tax activates the anaphase promoting complex
HTLV-I Tax 激活后期促进复合体
基本信息
- 批准号:8056549
- 负责人:
- 金额:$ 27.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-06-23 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnaphaseAntimitotic AgentsApoptosisAttenuatedBiologicalCDK2 geneCell AgingCell CycleCell Cycle ProgressionCell LineCellsCollectionCyclin ACyclin BCyclin ECyclin-Dependent Kinase InhibitorDNADNA DamageDNA Double Strand BreakDNA FragmentationDNA Replication DamageDNA StructureDNA biosynthesisDNA damage checkpointDataDevelopmentDown-RegulationFundingGemininGene ExpressionGenomic InstabilityGrowthHela CellsHumanHuman T-lymphotropic virus 1Human T-lymphotropic virus 2IndividualInfectionLeadLicensingLicensing FactorLiteratureMalignant NeoplasmsMediatingMessenger RNAMetaphaseMitosisMitoticMolecularNuclearOncogene ProteinsOncogenicParalysedPhenotypePlayPolyubiquitinationPreventionProductionProtein BindingProtein p53Replication LicensingReportingRepressionRoleS PhaseT-Cell LeukemiaT-LymphocyteTaxesTelomeraseTestingTropical Spastic ParaparesisUbiquitinationUp-RegulationViralViral GenesVirusanaphase-promoting complexcell transformationestablished cell linehuman PTTG1 proteininhibitor/antagonistinsightinterestleukemia/lymphomaleukemogenesismRNA Stabilitymicronucleusmutantnervous system disorderosteosarcomaprematurepreventpromoterpublic health relevancesenescencetreatment strategyubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 oncoprotein Tax is known to induce DNA damage, micronuclei formation, multinucleation, and DNA aneupoidy. The genomic instability induced by Tax is thought to play an important role in ATLL development. We have shown that the Tax can activate the anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls metaphase to anaphase transition and mitotic exit. APC/C activation by Tax leads to premature poly- ubiquitination and degradation of cell cycle regulators including cyclin A, cyclin B, securin, and Skp2. Skp2 is the substrate-targeting subunit of another E3 ligase known as SCFSkp2, which mediates the destruction of cyclin E/A-CDK2 inhibitor (CKI), p27. The degradation of Skp2 by APC/C as induced by Tax leads to SCFSkp2 inactivation and p27 stabilization. The mRNA level of another CKI, p21, also increases sharply as a result of promoter activation by Tax and mRNA stabilization due to Tax-induced APC/C activation. The massive surge in p21 and p27 in turn induces rapid senescence (Tax-IRS). Importantly, HeLa and SupT1 T cells infected by HTLV-1 arrest in senescence as well. By contrast, cells deficient in p21 and p27, such as HOS, escaped Tax- IRS and continue to divide after HTLV-1 infection or Tax expression. They however developed dramatic multinucleation and double-stranded DNA breaks, most likely as a result of constitutive APC/C activation. As might be expected, p27 is down-regulated and p21, mis-localized, in HTLV-1-transformed T (HTxT) cells which express Tax abundantly. The p21 and p27 deficiencies apparently allow HTxT cells to overcome Tax-induced senescence. Consistent with the idea that precocious activation of APC/C is deleterious to the cell, we recently found that the prototypic HTxT cell line, MT4, in addition to p21 and p27 deficiencies, expressed a much lower level of Cdh1, the substrate-targeting subunit of APC/C. Recent data from multiple labs indicate that premature APC/C activation through the depletion of Emi1, the S/G2 inhibitor of APC/C, disrupts Cdt1-geminin imbalance and promotes re-replication of DNA. The aberrant DNA replication (re-/hyper-replication) in turn causes multinucleation, double-stranded DNA breaks and DNA damage checkpoint activation. Emi1 depletion also results in premature degradation of Skp2 by APC/C, p27 stabilization, and senescence. Remarkably, the cell cycle phenotypes of Emi1 knockdown resemble those of Tax. These new findings validate our observations and raise many more interesting questions that will be addressed in the following three specific aims: aim 1, to elucidate the mechanism by which Tax activates APC/C; aim 2, to investigate the biological consequences of Tax-mediated APC/C activation; and aim 3, to determine how transformed T cells adapt to Tax expression.
PUBLIC HEALTH RELEVANCE: Human T-lymphotropic virus type I (HTLV-1) infects more than 20 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia and a paralytic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis. This project will elucidate the mechanism by which HTLV-1 oncoprotein Tax disrupts cellular control over DNA replication and induces senescence. The study will provide molecular insights that can lead to the development of treatment strategies for human cancer.
描述(申请人提供):HTLV-I是成人T细胞白血病/淋巴瘤(ATL)的病原体。已知HTLV-1癌蛋白税可导致DNA损伤、微核形成、多核和DNA异倍体。由税收引起的基因组不稳定性被认为在ATL的发育中起着重要作用。我们已经证明,TAX可以激活后期促进复合体/环体(APC/C),这是一种E3泛素连接酶,控制着中期到后期的过渡和有丝分裂的退出。税收激活APC/C导致多泛素化提前和细胞周期调节因子降解,包括细胞周期蛋白A、细胞周期蛋白B、细胞周期蛋白Securin和细胞周期蛋白Skp2。Skp2是另一种被称为SCFSkp2的E3连接酶的底物靶向亚基,它介导周期蛋白E/A-CDK2抑制物(CKI)p27的破坏。税收诱导的APC/C对Skp2的降解导致SCFSkp2失活和p27稳定。另一种CKI p21的mRNA水平也因Tax激活启动子而急剧增加,而Tax诱导的APC/C激活则使mRNA稳定。P21和p27的大量增加进而导致快速衰老(Tax-IRS)。重要的是,感染HTLV-1的HeLa和SupT1 T细胞也能阻止衰老。相反,p21和p27缺陷的细胞,如HOS,逃脱了Tax-IRS,并在HTLV-1感染或Tax表达后继续分裂。然而,它们发生了戏剧性的多核和双链DNA断裂,很可能是结构性APC/C激活的结果。不出所料,在大量表达Tax的HTLV-1转化的T(HTxT)细胞中,p27下调,p21错误定位。P21和p27的缺失显然允许HTxT细胞克服税收诱导的衰老。与早熟激活APC/C对细胞有害的观点一致,我们最近发现,典型的HTxT细胞系MT4,除了p21和p27缺陷外,还表达低水平的CDH1,这是APC/C的底物靶向亚基。最近来自多个实验室的数据表明,APC/C的过早激活是通过耗尽APC/C的S/G2抑制物Emi1,破坏CDT1-Gminin失衡,促进DNA的重新复制。异常的DNA复制(重新/超复制)反过来导致多核、双链DNA断裂和DNA损伤检查点激活。Emi1缺失还会导致Skp2通过APC/C过早降解、p27稳定和衰老。值得注意的是,Emi1基因敲除的细胞周期表型与Tax相似。这些新的发现证实了我们的观察,并提出了更多有趣的问题,这些问题将在以下三个具体目标中得到解决:目标1,阐明Tax激活APC/C的机制;目标2,研究Tax介导的APC/C激活的生物学后果;以及目标3,确定转化的T细胞如何适应Tax的表达。
公共卫生相关性:人类T淋巴细胞病毒I型(HTLV-1)感染全球2000多万人。相当大比例的感染者会患上成人T细胞白血病和一种被称为HTLV-1相关性脊髓病/热带痉挛瘫痪的麻痹性神经疾病。该项目将阐明HTLV-1癌蛋白Tax扰乱细胞对DNA复制的控制并诱导衰老的机制。这项研究将提供分子洞察力,有助于开发人类癌症的治疗策略。
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)
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CHOU-ZEN GIAM其他文献
CHOU-ZEN GIAM的其他文献
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{{ truncateString('CHOU-ZEN GIAM', 18)}}的其他基金
HTLV-1 Replication/Reactivation-Induced DNA Damage: Mechanisms and Pathogenesis
HTLV-1 复制/重新激活诱导的 DNA 损伤:机制和发病机制
- 批准号:
10572907 - 财政年份:2022
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8052727 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8607791 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8396677 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
7866744 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8448784 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8265753 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8214695 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8791965 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
Cell Cycle Regulation and Adult T Cell Leukemia
细胞周期调节和成人 T 细胞白血病
- 批准号:
8607461 - 财政年份:2010
- 资助金额:
$ 27.82万 - 项目类别:
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