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
• 负责人: CHOU-ZEN GIAM
• 金额: $ 30.8万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 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/8214695
• 关键词: Address; Adult; Affect; Anaphase; Aneuploidy; Biological; CD4 Positive T Lymphocytes; CDK2 gene; CDKN1A gene; 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; Hela Cells; Human; Human T-lymphotropic virus 1; Individual; Infection; 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

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(申请人提供)：HTLV-I是成人T细胞白血病/淋巴瘤(ATL)的病原体，ATL是一种CD4+T细胞的恶性肿瘤，其病因与病毒反式激活因子/癌蛋白TAX有关。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，并导致细胞周期蛋白A、细胞周期蛋白B、Securin和Skp2等有丝分裂调节因子降解。Skp2是另一种被称为SCFSkp2的E3泛素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基因p21的mRNA水平也因启动子的激活和Tax的稳定而急剧增加。P21和p27的大量表达导致细胞衰老，称为税收诱导的快速衰老(Tax-Induced Rapid Fastage，Tax-IRS)。不出所料，HTLV-1感染的HeLa和SupT1 T细胞也停止了衰老。相反，p21和p27缺陷的细胞，如HOS，在HTLV-1感染或Tax表达后逃脱Tax-IRS并继续分裂。然而，它们以多核和DNA非整倍体的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Tax的HTLV-1转化的T(HTxT)细胞中很常见，很可能是通过激活PI3K-Akt通路发生的。我们的最新结果表明，在S/G2期间，税收导致了DNA复制许可因子CDT1的显著积累。在一个最令人兴奋的最新发展中，我们发现，税收抑制核因子-βB的激活完全取消了税收-IRS。我们的发现提出了几个重要的问题：持续的NF-B激活是如何导致p21/p27上调和衰老的？核因子？B的激活是否位于APC/C激活和CDT1积聚的上游？税收诱导的CDT1的积累是否导致DNA重新/超复制，它能否解释在Tax表达细胞中所看到的戏剧性的核异常？最后，HTLV-1在SupT1和HeLa细胞中诱导的衰老样停滞表明，感染HTLV-1的原代T细胞可能也经历了衰老。如果是这样，那么导致衰老的病毒是如何导致白血病的呢？HTxT细胞系如何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，人们提出了三个特定的目标：(1)描绘由TAX持续激活的NF-B到衰老的途径；(2)研究HTLV和TAX诱导的染色体不稳定的原因和生物学效应；(3)阐明细胞对TAX和HTLV-1适应的机制。 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感染影响细胞分裂周期进展的机制，以及这些变化如何影响白血病的发展。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