Cell Cycle Regulation and Adult T Cell Leukemia

细胞周期调节和成人 T 细胞白血病

基本信息

批准号：
7866744
负责人：
CHOU-ZEN GIAM
金额：
$ 31.09万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7866744
关键词：
Address Adult Affect Anaphase Aneuploidy Biological CD4 Positive T Lymphocytes Cell Aging Cell Cycle Cell Cycle Regulation Cell Line Cell Proliferation Cells Chromosomal Instability Cyclin A Cyclin B Cyclin E DNA DNA Damage DNA biosynthesis Development Down-Regulation Etiology G2 Phase HTLV-1 Infection Hela Cells Human Human T-lymphotropic virus 1 Individual Lead Licensing Factor Malignant Neoplasms Mediating Messenger RNA Metaphase Mitotic Molecular Nuclear Oncogene Proteins Paralysed Pathway interactions Phosphorylation Proteins Ras/Raf Replication Licensing Role Signal Pathway Spinal Cord Diseases T-Cell Leukemia T-Cell Transformation T-Lymphocyte Taxes Testing Time Trans-Activators Tropical Spastic Paraparesis Ubiquitination Up-Regulation Viral Virus anaphase-promoting complex cell transformation human PTTG1 protein inhibitor/antagonist insight leukemia leukemia/lymphoma nervous system disorder osteosarcoma premature prevent promoter public health relevance senescence treatment strategy ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4+ T cells whose etiology is associated with the viral transactivator/oncoprotein, Tax. We have shown that 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 the premature poly-ubiquitination and degradation of mitotic regulators including cyclin A, cyclin B, securin, and Skp2. Skp2 is the substrate-targeting subunit of another E3 ubiquitin 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 and mRNA stabilization by Tax. The great surge in p21 and p27 in turn induces cellular senescence termed Tax-induced rapid senescence (Tax-IRS). As expected, 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, escape Tax-IRS and continue to divide after HTLV-1 infection or Tax expression. They, however, develop dramatic nuclear abnormalities in the form of multinucleation and DNA aneuploidy. Importantly, down-regulation of p27 and mis-localization of p21 are common in Tax-expressing HTLV-1-transformed T (HTxT) cells and most likely occur through activation of the PI3K- Akt pathway. Our latest results showed that Tax caused significant accumulation of the DNA replication licensing factor, Cdt1, during S/G2. In a most exciting recent development, we found that inhibition of NF-?B activation by Tax completely abrogated Tax-IRS. Our findings raise several important questions: How does persistent NF-?B activation lead to p21/p27 upregulation and senescence? Does NF-?B activation lie upstream of APC/C activation and Cdt1 accumulation? Does the accumulation of Cdt1 induced by Tax lead to DNA re/hyper-replication and can it explain the dramatic nuclear abnormalities seen in Tax-expressing cells? Finally, the senescence-like arrest induced by HTLV-1 in SupT1 and HeLa cells suggests that primary T cells productively infected by HTLV-1 likely also undergo senescence. If so, then how does a virus that induces senescence cause leukemia? How do HTxT cell lines manage to adapt to Tax and continue to divide? To address these questions and to elucidate the pathway by which HTLV-1 infection leads to T cell transformation and ATL, three specific aims are proposed: (1) to delineate the pathway leading from persistent NF-?B activation by Tax to senescence; (2) to investigate the cause and biological effects of HTLV- and Tax-induced chromosome instability; and (3) to elucidate the mechanisms by which cells become adapted to (transformed by) Tax and HTLV-1. 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 infection affects the progression of cell division cycle and how these changes impact on the development of leukemia. The study will provide molecular insights that can lead to the development of treatment strategies for human cancer

描述（由申请人提供）：HTLV-I是成人T细胞白血病/淋巴瘤（ATL）的病因，这是CD4+ T细胞的恶性肿瘤，其病因与病毒式反式激活器/癌蛋白，税收有关。我们已经表明，税收可以激活后期促进复合物/循环体（APC/C），这是一种E3泛素连接酶，将中期控制到后期转变和有丝分裂出口。通过税收激活的APC/C激活导致包括细胞周期蛋白A，细胞周期蛋白B，Securin和SKP2在内的有丝分裂调节剂的过早聚泛素化和降解。 SKP2是另一个E3泛素连接酶的底物靶向亚基，称为SCFSKP2，它介导了细胞周期蛋白E/A-CDK2抑制剂（CKI）的破坏，P27。税收引起的APC/C降解SCFSKP2失活和p27稳定。另一个CKI的mRNA水平P21的mRNA水平也因税收启动子的激活和mRNA稳定而急剧增加。 P21和P27的巨大激增反过来诱导了细胞衰老，称为税收引起的快速衰老（税务IR）。如预期的那样，HELA和SUPT1 T细胞也被HTLV-1在衰老中被阻止。相比之下，缺乏p21和p27的细胞，例如HOS，逃避税收IR，并在HTLV-1感染或税收表达后继续分裂。但是，它们以多核和DNA非整倍性的形式形式发展出戏剧性的核异常。重要的是，p27的下调和p21的错误定位在表达税收HTLV-1转化的T（HTXT）细胞中很常见，并且很可能通过激活PI3K-AKT途径而发生。我们的最新结果表明，在S/G2期间，税收导致DNA复制许可因子CDT1的大量积累。在最近的最令人兴奋的发展中，我们发现，通过税收抑制NF-？B的激活完全消除了税收。我们的发现提出了几个重要问题：持续的NF-？B激活如何导致P21/P27上调和衰老？ NF-？B激活是否位于APC/C激活和CDT1积累的上游？税收诱导的CDT1的积累是否导致DNA重复/过度复制，并且能解释出表达税收的细胞中显着的核异常吗？最后，HTLV-1在SUPT1和HELA细胞中诱导的衰老样停滞表明，由HTLV-1产生有效感染的原代T细胞也可能发生衰老。如果是这样，那么诱导衰老的病毒如何引起白血病？ HTXT细胞系如何设法适应税收并继续分裂？为了解决这些问题并阐明HTLV-1感染导致T细胞转化和ATL的途径，提出了三个具体目标：（1）描绘出从持续的NF- b激活通过税收到衰老的途径；（2）研究HTLV和税收诱导的染色体不稳定性的原因和生物学作用；（3）阐明细胞适应（通过）税收和HTLV-1的机制。公共卫生相关性：人类的T淋巴病毒I型（HTLV-1）在全球感染了超过2000万人。受感染的个体很大一部分会发展为成人T细胞白血病和一种被称为HTLV-1相关的脊髓病/热带痉挛性瘫痪的麻痹神经系统疾病。该项目将阐明HTLV-1感染影响细胞分裂周期发展的机制以及这些变化如何影响白血病的发展。该研究将提供分子见解，从而导致人类癌症治疗策略的发展